CN104056278B - 1,2,4-oxadiazole benzoic acid compounds - Google Patents

1,2,4-oxadiazole benzoic acid compounds Download PDF

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CN104056278B
CN104056278B CN201410119475.2A CN201410119475A CN104056278B CN 104056278 B CN104056278 B CN 104056278B CN 201410119475 A CN201410119475 A CN 201410119475A CN 104056278 B CN104056278 B CN 104056278B
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base
diazole
benzoic acid
phenyl
fluoro
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CN104056278A (en
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G.M.卡普
S.王
G.-M.陈
N.G.阿尔姆斯蒂德
Y-C.穆
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Ptc Treats Co
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Abstract

Novel 1,2,4-oxadiazole benzoic acid compounds, methods of using and pharmaceutical compositions comprising an 1,2,4-oxadiazole benzoic acid derivative are disclosed. The methods include methods of treating or preventing a disease ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay, or ameliorating one or more symptoms associated therewith.

Description

1,2,4- oxadiazole benzoic acid compounds
The application is divisional application, and the applying date of original application is on April 9th, 2004, Application No. 200480015905.0, Invention entitled " 1,2,4- oxadiazole benzoic acid compounds ".
1. invention field
The present invention relates to 1,2,4- oxadiazole benzoic acid compounds, containing the compositionss of described compound and give these changes Compound or composition treatment or the method preventing the disease relevant with mrna nonsense mutation.
2. background of invention
The gene expression of cell depends on the sequence measurement of transcription and translation.Meanwhile, these methods are from its related gene Nucleotide sequence in generate albumen.
Transcription is related to synthesize mrna by rna polymerase by dna.Transcription starts from the promoter region of gene, and continues Form loop-stem structure to for example newborn rna or rho gene outcome combines and induces termination.
Then with the help of trna, trna synzyme and various other albumen and rna class, ribosomal by betiding Translation process, generates albumen by mrna.Translation includes initial, extension and terminates three phases.By formed by protein factor, Translating equipment is instructed to start the startup of the ribosomal subunit composition of the signal of translation on mrna, trna, cofactor and identification mrna Complex, starts translation.
Starting complex once being formed, repeating to add ammonia by ribosomal peptidyl transferase activity and trna and trna synzyme Base acid, produces the growth of polypeptide chain.There is first sending of three termination codon (uaa, uag, uga) in ribosomal a position Signal, makes polypeptide chain release factors (rfs) combine and identify termination signal.Then, positioned at the 3 ' nucleoside of the trna of ribosome p position Ester bond between acid and nascent polypeptide chain is hydrolyzed.Established polypeptide chain is released, and described ribosomal subunit enters another Translation circulation.
The dna series jump that base number has change is divided into insertion or deletion mutation (frameshift mutation), and may result in main Genome destroy.Make the dna mutation that a base is changed into another base be referred to as missense mutation, and be subdivided into conversion (purine becomes pyrimidine, and pyrimidine becomes for (purine becomes another purine, or a pyrimidine becomes another pyrimidine) and transversion Purine).
Insertion, disappearance, conversion and transversional mutation all may result in nonsense mutation or chain terminating mutation, base mutation therein or Frameshift mutation makes amino acid codes become one of three kinds of termination codoies.Because these Premature stop codon terminate turning in advance Translate, paraprotein can be produced in cell.Nonsense mutation in highly important gene can be lethal, also can cause multiple Disease, such as cancer, lysosomal storage disease, muscular dystrophy, cystic fibrosises and hemophilia.
In the antibacterial and eucaryotic cell strain having nonsense mutation, because the mutation of one of trna molecule makes mutation trna can recognize that Nonsense codon, participate in the change change of albumen of translation process, the mutation of ribosome (ribosomal rna or ribosomal protein) or plus Enter the known compound (for example, cycloheximide or aminoglycoside antibioticss) changing translation process, nonsense mutation can be caused Suppression.As a result, aminoacid can be incorporated on the nonsense mutation site of polypeptide chain, and translation will not prematurely terminate at nonsense password Son.The aminoacid being inserted need not be identical with the Original amino of wild-type protein；However, many aminoacid replacement are tied to albumen Structure or function will not produce and have a strong impact on.Therefore, the albumen by suppressing nonsense mutation to produce is likely to be of close to wild type egg Such activity in vain.This situation is to avoid translation to terminate in advance by suppressing nonsense mutation, and treatment is relevant with nonsense mutation Disease provides chance.
Aminoglycoside antibioticses improve eukaryote termination codon read over ability, made us to these medicines as by The potential medicine of the disease of the people that nonsense mutation causes is interested.A kind of disease being applied to this therapeutic scheme is typical case Infantile neuronal ceroid lipofuscinosis (lincl) --- be unable to the fatal childhood neural degeneration of effectively treatment at present Property disease.Premature stop codon mutations in lysosome tripeptides peptidase 1 (tpp-i) encoding gene cln2 and examining close to half Break the child lincl disease relevant.It has been determined that aminoglycoside gentamycin recovers tpp-1 in lincl cell line The ability of activity.A kind of in the cell line of patient, this cell line is common nonsense mutation (arg208stop) and not With the heterozygote of rare nonsense mutation, at most recover the tpp-i of about 7% normal level with gentamicin treatment.These results Show may there is treatment potentiality with pharmacology's suppression that the similar medicine of aminoglycoside or effect carries out nonsense mutation to lincl (sleat etc., eur.j.ped.neurol.5:suppl a57-62 (2001)).
In the cultured cells having Premature stop codon in cftr protein (cftr) gene, use Aminoglycoside treatment leads to generate total length cftr (bedwell etc., nat.med.3:1280-1284 (1997)；Howard etc. .nat.med.2:467-469 (1996)).It was observed that gentamycin sulfate presses down in the mouse model of duchenne muscular dystrophy Translation termination processed in Premature stop codon, generate total length dystrophin (barton-davis etc., j.clin.invest.104∶375-381(1999)).A small amount of increase of the amount of total length dystrophin protects mdx mice not By injuring that contracture induces.The aminoacid being inserted in nonsense codon position is not determined in these researchs.
Suppress to translate the small molecule therapy agent terminating in advance or preventive to many by mediating misreading of nonsense codon The treatment planting disease is useful.Small-molecule drug, the discovery of especially oral bioavailable medicine can introduce wide spectrum Selective therapy agent, they can be used for resisting the disease being caused by nonsense mutation.
3. summary of the invention
The present invention includes noval chemical compound, novel pharmaceutical compositions and new treatment.Described compound, compositionss and method portion Divide the regulation that ground is decayed based on the mrna translation worked in various diseases being terminated in advance and/or nonsense mutation mediates. This kind of disease is because the termination in advance of translation leads to the minimizing of the amount of generated activated protein to occur.The change of the present invention Compound makes mrna translate continuous across nonsense mutation, generates full-length proteins.Therefore, the present invention includes treating and preventing multiple diseases The compound of disease, particularly genetic diseasess, compositionss and method.
The present invention includes 1,2,4- oxadiazole benzoic acid compounds or its pharmaceutically acceptable salt, hydrate, the bag of formula i Compound, prodrug, polymorph, stereoisomer, mix including enantiomer, diastereomer, racemic modification or stereoisomer Compound:
Wherein:
Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, replacement Or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl alkane Base；
r1It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl ,-(ch2ch2)nor6Or any can biological hydrolysis base Group；
r2、r3、r4、r5And r6Stand alone as hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, replacement or Unsubstituted alkynyl；Substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, Substituted or unsubstituted heteroaryl, alkoxyl, aryloxy group, heteroaryloxy, halogen, cf3、ocf3、ochf2、cn、cooh、coor7、 so2r7、no2、nh2Or n (r7)2；
Each r7Stand alone as hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynes Base；Substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, replacement or do not take The heteroaryl in generation, alkoxyl, aryloxy group, heteroaryloxy, halogen or cf3；With
N is the integer of 1-7.
In the relevant embodiments, the present invention includes the 1 of formula ii, 2,4- oxadiazole benzoic acid compounds
Or its pharmaceutically acceptable salt, hydrate, clathrate or stereoisomer, z therein as defined in formula i, r It is hydrogen or halogen.
In the preferred embodiments of the invention, the compound of formula i and ii is pharmaceutically acceptable salt, hydrate, inclusion Thing, prodrug, polymorph, the stereoisomer of ester, racemic modification or purification of biological hydrolysis can include, but not limited to optics Pure enantiomer and diastereomer.
Present invention additionally comprises by the treatment adjusting the disease that the mrna decay translating termination in advance or nonsense mediation is alleviated Or prevention method, or the method alleviating one or more symptom related to this, it include giving patient in need's treatment or Formula i of prevention effective dose or ii compound and its pharmaceutically acceptable salt, hydrate, solvate, clathrate, prodrug or many Crystal formation thing.In preferred embodiments, described disease is genetic diseasess；Cns disease；Inflammatory diseasess；Neurodegenerative disease；From Body immune disease；Proliferative disease, particularly cancer；Cardiovascular disease；Or pneumonopathy；More preferably disease includes, but not limited to Amyloidosis, lincl, hemophilia, Alzheimer, atherosclerosiss, giantism, dwarfism, thyroid machine Can go down, hyperthyroidism, cystic fibrosises, aging, obesity, parkinson, Niemann's disease, cystic fibrosises, Familial hypercholesterolemia, retinitis pigmentosa, duchenne muscular dystrophy or Marfan's syndrome.
Present invention additionally comprises treatment, prevention or alleviate one or more symptom relevant with genetic diseasess or genetic diseasess The method of clinical manifestation, it includes giving formula i or ii compound and its medicine of patient in need's treatment or prevention effective dose Acceptable salt, hydrate, solvate, clathrate, prodrug or polymorph on.In preferred embodiments, described Disease is cns disease；Inflammatory diseasess；Neurodegenerative disease；Cardiovascular disease；Autoimmune disease；Cancer；More preferably lose Pass disease, include, but not limited to amyloidosis, lincl, hemophilia, Alzheimer, atherosclerosiss, huge abnormal Shape, dwarfism, hypothyroidism, hyperthyroidism, cystic fibrosises, aging, obesity, parkinson, Buddhist nun Man disease, cystic fibrosises, familial hypercholesterolemia, retinitis pigmentosa, duchenne muscular dystrophy or Malaysia side Cotard.
The invention still further relates to the side for the treatment of, prevention or alleviation cancer or one or more symptom associated therewith or its performance Method, it includes giving formula i of patient in need's treatment or prevention effective dose or ii compound and its pharmaceutically acceptable Salt, hydrate, solvate, clathrate, prodrug or polymorph.
In the preferred embodiments of the invention, described patient is mammal, is more preferably susceptible to suffer from or has acquisition heredopathia wind The people of danger.In another embodiment, described patient, through screening process, determines that nonsense mutation exists, it is included with being subjected to The nonsense mutation screening test step of screening patient or the cell therefrom extracting.In related embodiment, described treatment Mark mark, wherein said patient screens through nonsense mutation screening test, by giving the compound of one or more present invention Treatment；Especially, for example, according to disease type, cell type and described gene, controlled with the compound being particularly suitable for described mutation Treat described patient.In yet another embodiment, described patient is baby or child.In another embodiment, the present invention includes Anemia of pregnant woman or the direct treatment of fetus.
In another preferred embodiment of the present invention, parenterally, transdermal, mucosa, nose, oral cavity, Sublingual or be administered orally to Give described compound；It is highly preferred that described compound is administered orally, most preferably, being administered orally is in the described of tablet, capsule or liquid form Compound.
The present invention includes translating the control method of the mrna decay of termination in advance and/or nonsense mediation.Present invention additionally comprises The suppressing method of the mrna decay of termination in advance and/or nonsense mediation is translated, it includes formula i or iiization with effective dose in cell Compound contact shows the cell of the mrna decay that translation terminates in advance and/or nonsense mediates.Present invention additionally comprises in cell The method of inducing nonsense suppression, it includes contacting, with formula i of effective dose or ii compound, the cell showing nonsense mutation.Nonsense Codon may occur in which in dna or rna of any types cell, Lock-in or predisposition can become and produce.Therefore, institute of the present invention State cell and include zooblast, mammalian cell, the cell of bacterial cell, plant cell and virus infection.In an embodiment party In case, nonsense codon is present in for generations in dna.In another embodiment, nonsense codon results from mutation.
It is not limited to any particular theory, formula i or ii compound improve to be readed over the ability of termination codon and make it can be used for controlling Treat or prevent any disease causing wholly or in part through nonsense mutation.Due to the termination in advance of translation, the active egg being generated White amount declines and this kind of disease occurs.It is not limited to any particular theory, formula i or ii compound make the translation of mrna be continued above Nonsense mutation, causes the generation of full-length proteins.One strong aspect of the present invention is, the treatment of formula i or ii compound is lived Property need not to be there is to disease specificity, but any disease relevant with nonsense mutation to treatment or prevention is effective.Additionally, this The method of invention possibly has specific to patient.I.e. through screening, patient can determine whether this disease is relevant with nonsense mutation. If it is, they can use the compounds for treating of the present invention.
The compound of formula i and ii can be used for treating or prevents genetic diseasess.Available formula i or ii compounds for treating or prevention Genetic diseasess include cancer, autoimmune disease, hematopathy, collagen, diabetes, inflammatory diseasess or central nervous system's disease Disease.
3.1 definition
The result referring to be mutated for " translation terminates in advance " of this paper makes the codon relevant with aminoacid be changed into termination Codon.
" the mrna decay of nonsense mediation " for this paper refers to mediate the mrnas decay of the Premature stop codon containing translation Any mechanism.
" Premature stop codon " or " premature stop codon " for this paper refers to occurred termination codon and should be Codon corresponding with aminoacid.
" nonsense mutation " for this paper is the point mutation that codon corresponding with aminoacid is changed into termination codon.
" nonsense suppression " for this paper refers to suppression or the compacting of the mrna decay to premature translation and/or nonsense mediation.
" regulation to translation termination in advance and/or the mrna decay of nonsense mediation " for this paper refers to by changing nonsense The horizontal adjustment gene expression of suppression.For example, if the defective egg of the gene code with Premature stop codon will be improved White generation, that is, allow to read over the Premature stop codon of disease gene, the translation of producer, then translation terminates in advance And/or the regulation of the mrna decay of nonsense mediation needs to be adjusted up nonsense suppression.Whereas if will improve to have terminating in advance The decay of the mrna of codon, then the regulation of the mrna decay that translation terminates in advance and/or nonsense mediates needs to adjust downwards Nonsense suppresses.
Term " patient " for this paper refers to animal (for example, cow, horse, sheep, pig, chicken, turkey, Carnis Coturnicis japonicae, cat, Canis familiaris L., little Mus, rat, rabbit, Cavia porcelluss etc.), the preferably for example non-primate of mammal and primate (such as monkey and people), optimum Choose.In certain embodiments, described patient is baby, children and adolescents or adult.In one embodiment, by pre- Screening determines which kind of nonsense mutation described patient has.In another embodiment, determine that described patient suffers from by prescreening Nonsense mutation (that is, uaa, uga or uag).In still another embodiment, described patient is by bacterial cell (for example, bacillus pyocyaneus (pseudomonas aeruginosa) infects.In another embodiment, the cell of described patient is infected.
Unless otherwise stated, the term for this paper " replacement " refers to be replaced by 1-4 or the following substituent groups of more Group, for example, halogeno-group；Trifluoromethy；Trifluoromethoxy；Hydroxyl；Alkoxyl；Cycloalkyloxy；Heterocyclic oxy group；Oxo； Alkanoyl；Alkyl-carbonyl；Cycloalkyl；Aryl；Aryloxy group；Aralkyl；Alkanoyl epoxide；Cyano group；Azido；Amino；Alkyl ammonia Base；Arylamino；Aryl alkyl amino；Cycloalkyl amino；Heterocyclic amino group；Two on single and double substituted-amino, wherein amino take Dai Ji is selected from alkyl, aryl, aralkyl, alkanoylamino, aroylamino, aralkanoylamino, replaces alkanoylamino, takes For arylamino, replace aralkanoylamino, thiol, alkylthio group, arylthio, fragrant sulfanyl, cycloalkylthio, heterocyclethio, Alkylthiono, arylthiono, aralkyl thiocarbonyl group, alkyl sulphonyl, aryl sulfonyl, arylalkyl sulfonyl, sulfenyl Amino (for example, so2nh2), replace sulfonamido, nitro, carboxyl, carbamoyl (for example, conh2), substituted-amino formyl (for example, conh alkyl, conh aryl, conh aralkyl or two substituent groups wherein on nitrogen are selected from alkyl, aryl or aralkyl to base The example of base), alkoxy carbonyl, aryl, substituted aryl, guanidine radicals and heterocyclic radical such as indyl, imidazole radicals, furyl, thiophene Base, thiazolyl, pyrrolidinyl, pyridine radicals, pyrimidine radicals etc..As described above, substituent group therein itself also can be substituted further, This kind of substituent group being further substituted with is selected from halogen, alkyl, alkoxyl, aryl and aralkyl.In a specific embodiment, Term replacement does not refer to cyano group.
Unless otherwise stated, the term for this paper " alkyl " refers to there be 1-20 carbon atom, preferably 1-10 carbon atom, The saturated straight chain of preferably 1-4 carbon atom or branched non cyclic hydrocarbon.Representational straight chain saturated alkyl include methyl, ethyl, N-pro-pyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and positive decyl；And saturation branched alkyl include different Propyl group, sec-butyl, isobutyl group, the tert-butyl group, isopentyl, 2- methyl butyl, 3- methyl butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethylbutyl, 2,3- bis- Methyl amyl, 2,4- dimethyl amyl group, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- diformazan Base amyl group, 2,2- dimethylhexanyl, 3,3- dimethyl amyl group, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethyl penta Base, 3- ethyl pentyl group, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethyl pentyl group, 2- methyl -3- second Base amyl group, 2- methyl -4- ethyl pentyl group, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2- methyl -4- ethyl hexyl Base, 2,2- diethyl amyl group, 3,3- diethylhexyl, 2,2- diethylhexyl, 3,3- diethylhexyl etc..Alkyl can not taken Generation or substituted.Unsaturated alkyl includes following alkenyls and alkynyl.
Unless otherwise stated, the term for this paper " alkenyl " refers to there be 2-20 carbon atom, and more preferably 2-10 carbon is former Son, most preferably 2-6 carbon atom, comprise the straight or branched non-cyclic hydrocarbon of at least one carbon-to-carbon double bond.Representational straight chain With side chain (c2-c10) alkenyl include vinyl, pi-allyl, -1-butylene base,-crotyl, isobutenyl, -1- pentenyl, - Pentenyl, -3-methyl-1-butene base, -2- methyl-2-butene base, -2,3- dimethyl-crotyl, -1- hexenyl, -2- Hexenyl, -3- hexenyl, -1- heptenyl, -2- heptenyl, -3- heptenyl, -1- octenyl, -2- octenyl, -3- octene Base, -1- nonenyl, -2- nonenyl, -3- nonenyl, -1-decene base, -2- decene base, -3- decene base etc..The double bond of alkenyl Can not be conjugated with another unsaturated group or be conjugated.Alkenyl can be unsubstituted or substituted.
Unless otherwise stated, the term for this paper " alkynyl " refers to there be 2-20 carbon atom, more preferably 2-10 carbon atom, Most preferably 2-6 carbon atom, comprises the straight or branched non-cyclic hydrocarbon of at least one carbon-to-carbon triple bond.Representational straight chain and Side chain-(c2-c10) alkynyl includes acetenyl, propinyl,-ethyl acetylene base, -2-butyne base, -1- pentynyl,-valerylene base, -3- Methyl isophthalic acid-butynyl, -4- pentynyl, -1- hexin base, -2- hexin base, -5- hexin base, -1- heptynyl, -2- heptynyl, -6- Heptynyl, -1- octynyl, -2- octynyl, -7- octynyl, -1- n-heptylacetylene base, -2- n-heptylacetylene base, -8- n-heptylacetylene base, -1- decine Base, -2- decynyl, -9- decynyl etc..Three keys of alkynyl can be conjugated with another unsaturated group or be conjugated.Alkynyl can not by Replace or substituted.
Unless otherwise stated, the term for this paper " halogen " or " halogeno-group " refer to fluorine, chlorine, bromine or iodine.
Unless otherwise stated, the term for this paper " alkyl sulphonyl " refers to-alkyl-so3H or-so3- alkyl, wherein alkane Base is as defined above, including-so2-ch3、-so2-ch2ch3、-so2-(ch2)2ch3、-so2-(ch2)3ch3、-so2-(ch2)4ch3、- so2-(ch2)5ch3Deng.
Unless otherwise stated, the term for this paper " carboxyl " refers to "-cooh ".
Unless otherwise stated, the term for this paper " alkoxyl " refers to-o- (alkyl), and alkyl therein is as defined above, bag Include-och3、-och2ch3、-o(ch2)2ch3、-o(ch2)3ch3、-o(ch2)4ch3、-o(ch2)5ch3Deng.
Unless otherwise stated, the term for this paper " alkoxy carbonyl " refers to-c (=o) o- (alkyl), wherein alkyl as above Definition, including-c (=o) o-ch3、-c(=o)o-ch2ch3、-c(=o)o-(ch2)2ch3、-c(=o)o-(ch2)3ch3、-c(=o)o- (ch2)4ch3、-c(=o)o-(ch2)5ch3Deng.In preferred embodiments, described ester is can biological hydrolysis (that is, described ester body It is hydrolyzed into outward or in vivo carboxylic acid).
Unless otherwise stated, the term for this paper " alkoxyalkyl " refers to-(alkyl)-o- (alkyl), wherein each " alkane Base " stands alone as alkyl as defined above, including-ch2och3、-ch2och2ch3、-(ch2)2och2ch3、-(ch2)2o(ch2)2ch3 Deng.
Unless otherwise stated, the term for this paper " aryl " refers to the homocyclic aromatic ring containing 5-14 annular atom.Carbocyclic ring The annular atom of aryl is carbon atom entirely.Aromatic ring structure includes the compound of one or more ring structures, for example singly-, double-or three Cycle compound and benzo-fused carbon ring group such as 5,6,7,8- tetralyls etc..Preferably, described aryl is monocyclic or bicyclic. Representational aryl includes phenyl, tolyl, anthryl, fluorenyl, indenyl, base, phenanthryl and naphthyl.Isocyclic aryl can be unsubstituted Or it is substituted.
Unless otherwise stated, the term for this paper " heteroaryl " refers to containing 5-14 annular atom and annular atom contains at least One hetero atom, the preferably 1-3 heteroatomic carbocyclic ring aromatic ring independently selected from nitrogen, oxygen or sulfur.Heteroaryl ring structures include one The compound of individual or multiple ring structure, for example singly-, double-or tricyclic compound, and fused heterocycle moities.Representational heteroaryl There are triazolyl, tetrazole radical, di azoly, pyridine radicals, furyl, benzofuranyl, thienyl, benzothienyl, benzisoxa Oxazolyl, benzisothia oxazolyl, quinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl group, imidazole radicals, benzimidazolyl, thiophene Oxazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, cinnolines base, 2，3-benzodiazine base, quinazolyl, Benzoquinazole base, acridinyl, pyrimidine radicals and oxazolyl.Group can unsubstituted or quilt Replace.
Unless otherwise stated, the term for this paper " aryloxy group " refers to-o- aryl, and aryl therein is as defined above.Fragrant oxygen Base can be unsubstituted or substituted.
Unless otherwise stated, the term for this paper " aralkyl " refers to-(alkyl)-(aryl), alkyl therein and aryl As defined above, including but not limited to-(ch2) phenyl ,-(ch2)2Phenyl ,-(ch2)3Phenyl ,-ch (phenyl)2,-ch (phenyl)3、- (ch2) tolyl ,-(ch2) anthryl ,-(ch2) fluorenyl ,-(ch2) indenyl ,-(ch2) base ,-(ch2) naphthyl etc..
Unless otherwise stated, the term for this paper " heteroaryl alkyl " and refer to * (alkyl)-(heteroaryl), wherein alkyl and Heteroaryl is as defined above, including but not limited to ,-(ch2) pyridine radicals ,-(ch2)2Pyridine radicals ,-(ch2)3Pyridine radicals ,-ch (pyridine Base)2,-c (pyridine radicals)3、-(ch2) triazolyl ,-(ch2) tetrazole radical ,-(ch2) di azoly ,-(ch2) furyl ,-(ch2) benzene And furyl ,-(ch2) thienyl ,-(ch2) benzothienyl etc..
Unless otherwise stated, the term for this paper " aralkyl oxy " refers to-o- (alkyl)-(aryl), wherein alkyl and Aryl is as defined above, including but not limited to-o- (ch2)2Phenyl ,-o- (ch2)3Phenyl ,-o-ch (phenyl)2,-o-ch (phenyl )3、-o-(ch2) tolyl ,-o- (ch2) anthryl ,-o- (ch2) fluorenyl ,-o- (ch2) indenyl ,-o- (ch2) base ,-o- (ch2) Naphthyl etc..
Unless otherwise stated, the term for this paper " cycloalkyl " refers to have no carbon-to-carbon multiple bond containing carbon and hydrogen atom Monocyclic or multi-ring saturated rings.Cycloalkyl can be unsubstituted or substituted.The example of cycloalkyl includes, but not limited to (c3-c7) ring Alkyl, including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl, and saturated rings and bicyclic terpene.Cycloalkyl can not taken Generation or substituted.Cycloalkyl is preferably monocyclic or bicyclic.
Unless otherwise stated, the term for this paper " heterocyclic radical " refers to containing carbon and hydrogen atom, optionally has 1-4 multiple bond Monocyclic or multi-ring, and annular atom comprises at least one, the preferably 1-3 hetero atom being independently selected from nitrogen, nitrogen and sulfur.Heterocycle structure Including the compound containing one or more ring structures, for example singly-, double-or tricyclic compound.Heterocyclic radical is preferably monocyclic or double Ring.Representational heterocycle include, but not limited to morpholinyl, pyrrolidone-base, pyrrolidinyl, piperidyl, hydantoin base, penta Lactam group, Oxyranyle, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, Tetrahydro-thienyl, tetrahydro thiapyran base etc..Heterocycle can be unsubstituted or substituted.
Unless otherwise stated, the term for this paper " cycloalkyl oxy " refers to-o- (cycloalkyl), and wherein cycloalkyl is as above fixed Justice.
Unless otherwise stated, the term for this paper " cycloalkyl-alkyl epoxide " refers to-o- (alkyl)-(cycloalkyl), wherein Cycloalkyl and alkyl are as defined above, including but not limited to ,-o- cyclopropyl ,-o- cyclobutyl ,-o- cyclopenta ,-o- cyclohexyl ,-o- Suberyl etc..
Unless otherwise stated, the term for this paper " aminoalkoxy " refers to-o- (alkyl)-nh2, wherein alkyl is as above fixed Justice, including but not limited to-o-ch2-nh2、-o-(ch2)2-nh2、-o-(ch2)3-nh2、-o-(ch2)4-nh2、-o-(ch2)5-nh2 Deng.
Unless otherwise stated, the term for this paper " alkyl amino " refers to-nh (alkyl) or-n (alkyl) (alkyl), wherein Alkyl is as defined above, including but not limited to nhch3、-nhch2ch3、-nh(ch2)2ch3、-nh(ch2)3ch3、-nh(ch2)4ch3、- nh(ch2)5ch3、-n(ch3)2、-n(ch2ch3)2、-n((ch2)2ch3)2、-n(ch3)ch2ch3) etc..
Unless otherwise stated, the term for this paper " arylamino " refers to-nh (aryl), and aryl therein is as defined above, Including but not limited to-nh (phenyl) ,-nh (tolyl) ,-nh (anthryl) ,-nh (fluorenyl) ,-nh (indenyl) ,-nh (base) ,-nh (than piperidinyl) ,-nh (naphthyl) etc..
Unless otherwise stated, the term for this paper " aryl-alkyl amino " refers to-nh- (alkyl)-(aryl), wherein alkyl As defined above with aryl, including-nh-ch2- (phenyl) ,-nh-ch2- (tolyl) ,-nh-ch2- (anthryl) ,-nh-ch2- (fluorenes Base) ,-nh-ch2- (indenyl) ,-nh-ch2- (base) ,-nh-ch2- (pyridine radicals) ,-nh-ch2- (naphthyl) ,-nh- (ch2)2- (phenyl) etc..
Unless otherwise stated, the term for this paper " cycloalkyl amino " refers to-nh- (cycloalkyl), wherein cycloalkyl as above Definition, including-nh- cyclopropyl ,-nh- cyclobutyl ,-nh- cyclopenta ,-nh- cyclohexyl ,-nh- suberyl etc..
Unless otherwise stated, the term for this paper " aminoalkyl " refers to-(alkyl)-nh2, wherein alkyl is as defined above, Including-ch2-nh2、-(ch2)2-nh2、-(ch2)3-nh2、-(ch2)4-nh2、-(ch2)5-nh2Deng.
Unless otherwise stated, the term for this paper " alkylaminoalkyl group " refers to (alkyl)-nh (alkyl) or-(alkyl)-n (alkyl) (alkyl), wherein respectively " alkyl " stands alone as alkyl as defined above, including-ch2-nh-ch3、-ch2-nhch2ch3、- ch2-nh(ch2)2ch3、-ch2-nh(ch2)3ch3、-ch2-nh(ch2)4ch3、-ch2-nh(ch2)5ch3、-(ch2)2-nh-ch3、- ch2-n(ch3)2、-ch2-n(ch2ch3)2、-ch2-n((ch2)2ch3)2、-ch2-n(ch3)(ch2ch3)、-(ch2)2-n(ch3)2 Deng.
" therapeutically effective amount " for this paper refers to, in the process and treatment of disease, the compound of the present invention or other alive Property agent be enough to provide treatment benefit, to postpone or to reduce to greatest extent the amount of the symptom relevant with described disease.And, the present invention The therapeutically effective amount of compound refers to single therapy agent or the amount with other therapeutic agent, and described amount is in the treatment of disease and process Middle offer treatment benefit.When being used together with the amount of the compounds of this invention, term may include improvement and entirely treats, is reduced or avoided The symptom of disease or the cause of disease or another kind of curative effect of therapeutic agent of increase or the amount of effect in unison.
" prevention effective dose " for this paper refers to, and the compound of the present invention or other active component be enough to lead to prevention disease Recurrence or propagation amount.Prevention effective dose can refer to described amount and be enough to prevent patient, including but not limited to, be susceptible to suffer from described disease Those patients, fall ill or recur or spread disease.Prevention effective dose also can refer to be provided that prevention benefit in terms of disease prevention Amount.And, the prevention effective dose of the compounds of this invention is referred to single or is measured in combination with other medicines, and this amount is in the prevention of disease Middle offer prevents benefit.When together with using with the amount of the compounds of this invention, described term may include the whole prevention of improvement or promotes The preventive effect of another kind of prophylactic agent or the amount promoting effect in unison.
" therapeutic scheme " for this paper refers to the time of one or more medicine and dosage arranges scheme.
" prevention scheme " for this paper refers to the time of one or more prophylactic agent and dosage arranges scheme.
" scheme " for this paper includes dose plan and dosage.
" joint " for this paper refers to more than one prevention and/or the use of medicine.
Term " process " for this paper refers to patient and obtains beneficial effect from prevention or medicine, and it does not lead to The treatment of disease.In certain embodiments, give patient to prevent for one or more or medicine, with " process " disease, in advance Anti- advancing of disease or deterioration.
Term " prevention " for this paper refers to, and prevents the generation of patient disease, recurrence by giving prevention or medicine Or propagate.
Term " treatment " for this paper refers to eradicate or alleviates disease or the symptom related to described disease.In some enforcements In scheme, this term refers to by providing one or more prevention or medicine to subtract to greatest extent to the patient with this kind of disease Few transmission of disease or deterioration.
Term " pharmaceutically acceptable salt " for this paper refers to by pharmaceutically acceptable non-toxic acid or alkali, including inorganic Bronsted lowry acids and bases bronsted lowry and the salt of organic bronsted lowry acids and bases bronsted lowry preparation.The pharmaceutically acceptable base addition salts of applicable the compounds of this invention include, but It is not limited to, by the slaine of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc preparation, or by lysine, n, n '-dibenzyl-ethylenediamin, chloro Procaine, choline, diethanolamine, the organic salt of ethylenediamine, Mai Geluming (n- methylglucosamine) and procaine preparation.Suitable Non-toxic acid includes, but are not limited to inorganic and organic acid, such as acetic acid, alginic acid, ortho-aminobenzoic acid, benzenesulfonic acid, benzene first Acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid (ethenesulfonic), formic acid, fumaric acid, furancarboxylic acid, galacturonic acid, Fructus Vitis viniferae Saccharic acid, glucuronic acid, glutamic acid, glycolic, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, Methanesulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propanoic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, Sulphuric acid, tartaric acid and p-methyl benzenesulfonic acid.Concrete non-toxic acid includes hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and methanesulfonic acid.Thus having The example of body salt includes hydrochlorate and mesylate.Other examples of salt are known in the art, see, e.g., Remington ' s pharmaceutical sciences, the 18th edition, mack publishing, easton pa (1990).
Unless otherwise stated, the term for this paper " prodrug " refer to can under biotic factor (external or internal) hydrolysis, oxygen Change or reaction generates reactive compound, the particularly derivant of the compound of the compounds of this invention.The example of prodrug includes, but not Be limited to, the derivant of the compounds of this invention and metabolite, described compound include can biological hydrolysis group, for example can Biological water Solution amide, can biological hydrolysis ester, can biological hydrolysis carbamate, can biological hydrolysis carbonic ester, can biological hydrolysis Uride and can biological hydrolysis phosphate analogs.The prodrug of the compound with carboxyl functional group is preferably the lower alkyl of carboxylic acid Base ester.Carboxylate can be conveniently generated by being esterified any hydroxy-acid group present in molecule.Method known to typically using, for example Burger ' s medicinal chemistry and drug discovery the 6th edition (donald j.abraham edits, 2001, wiley) and design and application of prodrugs (h.bundgaard edits, 1985, harwood Academic publishers gmfh) described in those methods can prepare prodrug.
Unless otherwise stated, the term for this paper amide of biological hydrolysis " can ", the ester of biological hydrolysis " can ", " can give birth to The carbamate of thing hydrolysis ", the carbonic ester of biological hydrolysis " can ", the uride of biological hydrolysis " can ", " can biological hydrolysis phosphoric acid Ester " respectively refers to amide, ester, carbamate, carbonic ester, uride or the phosphate ester of compound, described compound or: 1) in vivo The not biological activity of interfering compound, but can give described compound excellent property, such as picked-up, continuous action or an action With；Or be 2) inactive but the compound of biological activity can be converted in vivo.Can biological hydrolysis ester Example includes, but not limited to lower alkyl esters, alkoxy-cyloxy esters, alkyl amido Arrcostab and cholinester.Can Biological water The example of the amide of solution, but be not limited to, lower alkyl, alpha-amino acid amides, alkoxyacyl amides and alkyl amino alkane Base carbonyl amide.The example of carbamate of biological hydrolysis can include, but not limited to low-grade alkylamine, substituted ethylene diamine, ammonia Base acid, hydroxy alkyl amine, heterocycle and heteroaryl amine and polyetheramine.
Unless otherwise stated, the term for this paper " optical voidness " or " stereoisomer is pure " refer to be substantially free of described chemical combination The stereoisomer of the compound of other stereoisomers of thing.For example, the stereoisomer purification having a chiral centre closes Thing can be substantially free of the reverse enantiomer of described compound.The stereoisomer pure compound having two chiral centres can substantially not Other diastereomers containing described compound.Typical stereoisomer pure compound comprises the institute of greater than about 80% weight State a kind of stereoisomer of compound and other stereoisomers of the described compound of below about 20% weight, preferably greater than A kind of other solids of the described compound of the stereoisomer of the described compound of about 90% weight and below about 10% weight Isomer, a kind of stereoisomer of the described compound of more preferably greater than about 95% weight and below about 5% weight described Other stereoisomers of compound, a kind of stereoisomer of the described compound of most preferably greater than about 97% weight and being less than Other stereoisomers of the described compound of about 3% weight.
Unless otherwise stated, the term for this paper " enantiomer-pure " refers to have the solid of the compound of a chiral centre different The pure compositionss of structure body.
If it is noted that having difference in described structure and the title giving described structure between, then described structure will be given Give more attention.And, the spatial chemistry of such as fruit structure or part-structure is not indicated with such as thick line or dotted line, then, Described structure or part-structure will be construed to comprise its all stereoisomers.
4. detailed Description Of The Invention
4.1 the compounds of this invention
The present invention includes the 1,2,4- oxadiazole benzoic acid compounds of formula i
Or its pharmaceutically acceptable salt, hydrate, clathrate, prodrug, polymorph, stereoisomer, including mapping The mixture of body, diastereomer, racemic modification or stereoisomer:
Wherein:
Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, replacement Or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl alkane Base；
r1It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl ,-(ch2ch2)nor6Or any can biological hydrolysis group；
r2、r3、r4、r5And r6Stand alone as hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, replacement or Unsubstituted alkynyl；Substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, Substituted or unsubstituted heteroaryl, alkoxyl, aryloxy group, heteroaryloxy, halogen, cf3、ocf3、ochf2、cn、cooh、coor7、 so2r7、no2、nh2Or n (r7)2；
Each r7Stand alone as hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, replacement when occurring every time Or unsubstituted alkynyl；Substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted virtue Base, substituted or unsubstituted heteroaryl, alkoxyl, aryloxy group, heteroaryloxy, halogen or cf3；With
N is the integer of 1-7.
In an optional embodiment, the present invention includes formula i compound, wherein works as r1、r2、r3、r4And r5During for hydrogen, Z is not methyl, 2- carboxy ethyl, 3- (4- pyridine radicals) propyl group or 2- (4- piperidyl) ethyl.
In a preferred embodiment, the present invention includes wherein r1Formula i compound for h.
In a preferred embodiment, the present invention includes wherein r1For be not h any can biological hydrolysis group formula iization Compound.
In the relevant embodiments, the present invention includes the 1 of formula ii, 2,4- oxadiazole benzoic acid compounds
Or its pharmaceutically acceptable salt, hydrate, clathrate or stereoisomer:
Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, replacement Or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl alkane Base；R is hydrogen or halogen.
In one embodiment, r is halogen, fluorine.In a preferred embodiment, r is hydrogen.
In a preferred embodiment, the present invention includes the compound of formula i or ii, and wherein z is p-methylphenyl；(4- chlorine For methylphenyl)；(the chloro- pyridin-3-yl of 2-)；(2- fluoro-phenyl)；(3,4- difluorophenyl)；(4- methoxyl group-phenyl)；Benzene And [1,3] dioxolyl；(4- Ethyl-phenyl)；O-tolyl；(the chloro- phenyl of 2-)；(3- methyl-thiophene -2- Base)；Benzo [b] thiophene -2- base；(3- fluoro-phenyl)；(4- tbutyl-phenyl)；(2- methoxyl group-phenyl)；(2, two fluoro- benzene Base)；Thiophene -2- base；(2,4- difluorophenyl)；(the chloro- phenyl of 3-)；Between tolyl；(4- trifluoromethvl-phenvl)；(4- is fluoro- Phenyl)；(3- methoxyl group-phenyl)；Phenyl；(2,6- difluoro-benzene base)；(2, dimethyl-furan -3- base)；(4- pyrroles -1- Base-phenyl)；(3- dimethyl-amino-phenyl)；Biphenyl -4- base；(4- dimethyl-amino-phenyl)；Benzo [1,2,5] diazole- Base；Between tolyl；(2- trifluoromethvl-phenvl)；(the chloro- pyridin-3-yl of 6-)；(3, double-trifluoromethvl-phenvl)；Furan- 2- base；(4- nitro-phenyl)；(3,4- dimethoxy-phenylf)；(3- trifluoromethoxy-phenyl)；Naphthalene -1- base；Cyclohexyl； Pyridin-3-yl；Pyridin-4-yl；Cyclopenta；Cyclopropyl；(4- amyl group epoxide-phenyl)；(3,4, trimethoxv-henvl)；(4- is different Butyl-hohenyl)；Cyclobutyl；(1- acetyl group-piperidin-4-yl)；Isoxazole-base；[(2- chloro- 6- fluoro-phenyl)-methyl-different Azoles -4- base] or [(the chloro- phenyl of 2-)-methyl-isoxazole -4- base]；Z is more preferably (3- fluoro-phenyl), and more preferably z is that (4- is fluoro- Phenyl), even more preferably z is (2- fluoro-phenyl).
In a specific embodiment, the present invention includes formula i or the ii compound that wherein z is not 4- cvano-phenyl.
Preferred compounds of the invention includes, but not limited to
1) 3- (5- p-methylphenyl-[1,2,4] diazole -3- base)-benzoic acid；
2) 3- [5- (4- chloromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
3) 3- [5- (the chloro- pyridin-3-yl of 2-)-[1,2,4] diazole -3- base]-benzoic acid；
4) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
5) 3- [5- (3,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid；
6) 3- [5- (4- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
7) 3- (5- benzo [1,3] dioxole -5- base-[1,2,4] diazole -3- base)-benzoic acid；
8) 3- [5- (4- Ethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
9) 3- (5- o-tolyl-[1,2,4] diazole -3- base)-benzoic acid；
10) 3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid；
11) 3- [5- (3- methyl-thiophene -2- base)-[1,2,4] diazole -3- base]-benzoic acid；
12) 3- (5- benzo [b] thiophene -2- base-[1,2,4] diazole -3- base)-benzoic acid；
13) 3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
14) 3- [5- (4- tbutyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
15) 3- [5- (2- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
16) 3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid；
17) 3- (5- thiophene -2- base-[1,2,4] diazole -3- base)-benzoic acid；
18) 3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid；
19) 3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid；
20) 3- (tolyl-[1,2,4] diazole -3- base between 5-)-benzoic acid；
21) 3- [5- (4- trifluoromethvl-phenvl)-[1,2,4] diazole -3- base]-benzoic acid；
22) 3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
23) 3- [5- (3- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
24) 3- (5- phenyl)-[1,2,4] diazole -3- base)-benzoic acid；
25) 3- [5- (2,6- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid；
26) 3- [5- (2,5- dimethyl-furan -3- base)-[1,2,4] diazole -3- base]-benzoic acid；
27) 3- [5- (4- pyrroles -1- base-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
28) 3- [5- (3- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
29) 3- (5- biphenyl -4- base-[1,2,4] diazole -3- base)-benzoic acid；
30) 3- [5- (4- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
31) 3- (5- benzo [1,2,5] diazole -5- base-[1,2,4] diazole -3- base)-benzoic acid；
32) 3- (tolyl-[1,2,4] diazole -3- base between 5-)-benzoic acid；
33) 3- [5- (2- trifluoromethvl-phenvl)-[1,2,4] diazole -3- base]-benzoic acid；
34) 3- [5- (the chloro- pyridin-3-yl of 6-)-[1,2,4] diazole -3- base]-benzoic acid；
35) 3- [5- (3,5- double-trifluoromethvl-phenvl)-[1,2,4] diazole -3- base]-benzoic acid；
36) 3- (5- furan -2- base-[1,2,4] diazole -3- base)-benzoic acid；
37) 3- [5- (4- nitro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
38) 3- [5- (3,4- dimethoxy-phenylf)-[1,2,4] diazole -3- base]-benzoic acid；
39) 3- [5- (3- trifluoromethoxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
40) 3- (5- naphthalene -1- base-[1,2,4] diazole -3- base)-benzoic acid；
41) 3- (5- cyclohexyl-[1,2,4] diazole -3- base)-benzoic acid；
42) 3- (5- pyridin-3-yl-[1,2,4] diazole -3- base)-benzoic acid；
43) 3- (5- pyridin-4-yl-[1,2,4] diazole -3- base)-benzoic acid；
44) 3- (5- cyclopenta-[1,2,4] diazole -3- base)-benzoic acid；
45) 3- (5- cyclopropyl-[1,2,4] diazole -3- base)-benzoic acid；
46) 3- [5- (4- amyl group epoxide-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
47) 3- [5- (3,4,5- trimethoxv-henvl)-[1,2,4] diazole -3- base]-benzoic acid；
48) 3- [5- (4- isobutvl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
49) 3- (5- cyclobutyl)-[1,2,4] diazole -3- base)-benzoic acid；
50) 3- [5- (1- acetyl group-piperidin-4-yl)-[1,2,4] diazole -3- base]-benzoic acid；
51) 3- (5- isoxazole -5- base-[1,2,4] diazole -3- base)-benzoic acid；
52) 3- { 5- [3- (2- chloro- 6- fluoro-phenyl) -5- methyl-isoxazole -4- base]-[1,2,4] diazole -3- base } - Benzoic acid；
53) 3- (5- isopropyl-[1,2,4] diazole -3- base)-benzoic acid；
54) 3- (the 5- tert-butyl group-[1,2,4] diazole -3- base)-benzoic acid；
55) 3- (5- butyl-[1,2,4] diazole -3- base)-benzoic acid；
56) 3- (5- acrylic-[1,2,4] diazole -3- base)-benzoic acid；
57) 3- [5- (the chloro- benzyl of 4-)-[1,2,4] diazole -3- base]-benzoic acid；
58) 3- [5- (the chloro- phenoxymethyl of 4-)-[1,2,4] diazole -3- base]-benzoic acid；
59) 3- (5- benzyl-[1,2,4] diazole -3- base)-benzoic acid；
60) 3- (5- methoxy)-[1,2,4] diazole -3- base)-benzoic acid；
61) 3- [5- (1- phenyl-propyl group)-[1,2,4] diazole -3- base]-benzoic acid；
62) 3- [5- (the fluoro- benzyl of 4-)-[1,2,4] diazole -3- base]-benzoic acid；
63) 3- [5- (the chloro- phenoxymethyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid；
64) 3- [5- (the chloro- pyridin-3-yl of 6-)-[1,2,4] diazole -3- base]-benzoic acid；
65) 3- (5- cyclopentyl-methyl-[1,2,4] diazole -3- base)-benzoic acid；
66) 3- [5- (4- methyoxy-benzyl)-[1,2,4] diazole -3- base]-benzoic acid；
67) 3- [5- (2,3- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid；
68) 3- [5- (2- fluoro- 5- methylphenyl)-[1,2,4] diazole -3- base]-benzoic acid；
69) 3- [5- (2- methylsulfanyl-pyridin-3-yl)-[1,2,4] diazole -3- base]-benzoic acid；
70) 3- [5- (2,2- bis- fluoro- benzo [1,3] dioxole -5- base)-[1,2,4] diazole -3- base] - Benzoic acid；
71) the fluoro- 3- of 4- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
72) the fluoro- 5- of 2- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
73) 3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
74) 3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
75) 3- [5- (3- fluoro- biphenyl -4- base)-[1,2,4] diazole -3- base]-benzoic acid；
76) 3- { 5- [3- (the chloro- phenyl of 2-) -5- methyl-isoxazole -4- base]-[1,2,4] diazole -3- base }-benzene first Acid；
77) 3- [5- (4- cvano-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
78) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt；
79) 3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe；
80) 5- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base] -2- methoxy-benzoic acid；
81) 3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
82) 3- [5- (3- fluoro- biphenyl -4- base)-[1,2,4] diazole -3- base]-benzoic acid；
83) 3- [5- (6- pyrrolidin-1-yl-pyridin-3-yl)-[1,2,4] diazole -3- base]-benzoic acid；
84) 3- [5- (6- morpholine -4- base-pyridin-3-yl)-[1,2,4] diazole -3- base]-benzoic acid；
85) 3- [5- (3,4,5,6- tetrahydrochysene -2h- [1,2 '] bipyridyls -5 ' base)-[1,2,4] diazole -3- base]-benzene first Acid；
86) 3- [5- (2- fluoro- 6- hydroxy-pheny)-[1,2,4] diazole -3- base]-benzoic acid；
87) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe；
88) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- methoxy acrylate；
89) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- Mehtoxy-ethoxy)-second Ester；
90) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- Mehtoxy-ethoxy) - Ethyoxyl]-ethyl ester；
91) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- { 2- [2- (2- methoxyl group-ethoxy Base)-ethyoxyl]-ethyoxyl }-ethyl ester；
92) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- { 2- [2- (2- methoxyl group-second Epoxide)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester；
93) 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- 2- [2- (2- hydroxyl - Ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyl ester；
94) 3- [5- (4- methanesulfonylamino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；
95) 3- [5- (4- azido-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；With
96) 3- [5- (4- benzyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid.
The compound of formula i and ii and ones listed above compound are referred to here as " the compounds of this invention ".Of the present inventionization The example of compound is described in table 1 below.
The determination of activity of table 1, examination are carried out with the luciferase reporter gene test (as described in 4.2 sections) based on cell Test the luciferase reporter gene structure containing uga Premature stop codon in 293t HEKC including stable transfection Become thing.Using known small molecule 3- [3- (4- isopropyl-phenyl) -2, the 5- dioxo-miaow allowing to read over Premature stop codon Oxazolidine -1- base]-benzoic acid be used as internal standard.Determination of activity is based on the required compound generating specified albumen in the cell On qualitative relationships between the maximum (effect) of the albumen of Cmin (effect) and Hemapoiesis.Effect and efficacy activities quilt It is divided into high, very high or notable grade.Combination using these activity determines Activity Rank.It is found to have the high of albumen synthesis The compound of effect and high effect is classified as " * * * * * ".It is found to have albumen synthesis and the very high effect of high effect Compound is classified as " * * * * ".The compound of the albumen synthesis and high effect that are found to have very efficient is classified as “****”.The compound being found to have very efficient and the very albumen synthesis of high effect is classified as " * * * ".It is found to have very high The compound of the albumen synthesis of effect and remarkable result is classified as " * * ".The albumen being found to have notable effect synthesizes and very high The compound of effect is classified as " * * ".Similarly, the compound being found to have the albumen synthesis of notable effect and effect is divided Class is " * " (referring to following table).
Effect Effect Grade
High High *****
High Very high ****
Very high High ****
Very high Very high ***
Very high Significantly **
Significantly Very high **
Significantly Significantly *
In the luciferin enzyme test based on cell, albumen synthesizes effect or effect or is both less than significant level Compound classifies as no asterisk.But it is believed that these compounds are useful in the vivo approaches of the present invention.
The present invention includes the external of the compounds of this invention or vivo purposes, and the compounds of this invention be attached to for treatment and Prevent in various diseases and the Pharmaceutical composition and single unit dosage form of disease.Disease specific and disease are included by courier Those of nonsense mutation suppression alleviation in rna.
Pharmaceutical composition includes dosage form of the present invention, and it comprises the compounds of this invention or its pharmaceutically acceptable polymorphic Thing, prodrug, salt, clathrate, solvate or hydrate, can be used in the method for the present invention.
It is not limited to theory it is believed that the compound scalable translation of the present invention terminates in advance and/or the mrna of nonsense mediation declines Become.Therefore, first embodiment of the present invention is related to translate the regulation side of the mrna decay of termination in advance and/or nonsense mediation Method, it includes the compounds of this invention or its pharmaceutically acceptable prodrug, metabolite, polymorph, salt, solvent with effective dose Compound, hydrate or clathrate contact show the cell of nonsense mutation.In a particular embodiment, the present invention relates to nonsense presses down The mediated method of system, it includes the compounds of this invention or its pharmaceutically acceptable prodrug, metabolite, polymorphic with effective dose Thing, salt, solvate, hydrate or clathrate contact show the cell of nonsense mutation.
4.2 biologic tests and zooscopy
Available multiple technologies identification adjusts the compound of the mrna decay that translation terminates in advance and/or nonsense mediates.For example, The screening technique adjusting the compound expressed after having the transcription of any gene of premature translation termination codon is described in the world Number of patent application wo01/44516a2, is incorporated herein by reference.In preferred embodiments, have and terminate in advance The mrna of codon is by In Vitro Translation, and is used to filler test compound library.In preferred embodiments, have and terminate in advance The mrna of codon is the reporter gene with Premature stop codon.
Develop for high flux screening, to differentiate two tests of the small molecule promoting nonsense suppression.Because this is work( Can test (just producing light only when albumen is functional) reporter gene, and extremely sensitive (luminous intensity and luciferase Concentration is proportional in the range of nm), so each test adopts luciferase.First test is the luciferin based on cell Enzyme reporter gene is tested, and second test is the luciferase reporter gene by rabbit reticulocyte lysates with containing nonsense The biochemical test of mrna composition.In the test based on cell, the luciferase report containing uga Premature stop codon Dao gene construct is stably transfected in 293t HEKC.In biochemical test, using being supplemented with trna, chlorination Haemachrome, creatine kinase, aminoacid, koac, mg (oac)2With the rabbit reticulocyte lysates of phosphagen, carry containing uga The mrna of front termination codon is used as the reporter gene in In Vitro Translation reaction.Start mrna with the targeting sequencing of virus induction Translation, this can substantially reduce the cost of test, because not needing hat shape rna.In vitro in transcript reagent box (ambion) Prepare synthesis mrna with t7 promoter and megascripr in vitro.In two tests in biochemistry with based on cell, Know allow to read over small molecule 3- [3- (4- isopropyl-phenyl) -2,5- Dioxo-imidazoliin -1- base] of Premature stop codon - Benzoic addition, leads to the increase of luciferin enzymatic activity, therefore, is used as internal standard.
Also can be with the safety of animal model system confirmation formula i or ii compound and effect.Formula i can be tested with animal model Or the biologic activity to described disease, disease or symptom for the ii compound.These include the target containing linkage function read-out system The genetic engineering modified animal of rna element, such as transgenic mice.
The example of the animal model of cystic fibrosises includes, but not limited to cftr (- /+) mice and (see, e.g., Freedman etc., 2001, gastroenterology121 (4): 950-7), cftr (tmlhgu/tmlhgu) mice is (referring to example As, bernhard etc., 2001, exp lung res27 (4): 349-66), have the mediation of defect camp- cl (-) electric conductivity Cftr- deficient mice (see, e.g., stotland etc., 2000, pediatr pulmonol30 (5): 413-24) and c57bl/ 6-cftr (mlunc)/cftr (mlunc) rejects mice and (see, for example, stotland etc., 2000, pediatr pulmonol30 (5): 413-24).
The example of the animal model of muscular dystrophy includes, but not limited to mice, hamster, cat, Canis familiaris L. and C. Elegans Automatic Screening (c.elegans).The example of the mouse model of muscular dystrophy includes, but not limited to dy-/- mice and (see, e.g., Connolly etc., 2002, j.neuroimmunol127 (1-2): 80-7), suffer from myositis muscular dystrophy (mdm) mice mutation (see, e.g., garvey etc., 2002, genomics79 (2): 146-9), mdx mice (see, e.g., nakamura etc., , 2001, neuromuscul disord11 (3): 251-9) utrophin- dystrophin reject (dko) mice (referring to, For example, nakamura etc., 2001, neuromuscul disord11 (3): 251-9), dy/dy mice (see, e.g., Dubowitz etc., 2000, neuromuscul disord10 (4-5): 292-8), mdx (cv3) mouse model (see, e.g., Pillers etc., 1999, laryngoscope109 (8): 1310-2) (see, e.g., with muscle tonus adr-mdx mutant mice Kramer etc., 1998, neuromuscul disord8 (8): 542-50).The example of the hamster suffering from muscular dystrophy includes, but It is not limited to, several sugar (sarcoglycan)-shortage property hamster (see, e.g., nakamura etc., 2001, am j physiol Cell physiol281 (2): c690-9) and bio14.6 malnutrition hamster (see, e.g., schlenker＆burbach, 1991, j appl physiol71 (5): 1655-62).The example of the feline model suffering from muscular dystrophy includes, but does not limit In loose cat family muscular dystrophy model (see, e.g., gaschen＆burgunder, 2001, acta neuropathol (berl) 101 (6): 591-600).The Canis animalss model suffering from muscular dystrophy includes, but not limited to the sleuth flesh battalion of gold Support bad (see, e.g., fletcher etc., 2001, neuromuscul disord11 (3): 239-43) and Canis animalss x- Related muscular dystrophy (see, e.g., valentine etc., 1992, am j med genet42 (3): 352-6).Suffer from myotrophy Bad C. Elegans Automatic Screening (c.elegans) model instance is described in chamberlain＆benian, 2000, curr biol10 (21): r795-7 and culette＆sattelle, 2000, hum mol genet9 (6): in 869-77.
Example for the animal model of familial hypercholesterolemia includes, but not limited to lack function ldl receptor base The mice (see, e.g., aji etc., 1997, circulation95 (2): 430-7) of cause, yoshida rat (see, e.g., Fantappie etc., 1992, life sci50 (24): 1913-24), jcr:la-cp rat (see, e.g., richardson Deng 1998, atherosclerosis138 (1): 135-46), pig (see, e.g., hasler-rapacz etc., 1998, am j Med genet76 (5): 379-86) and watanabe heritable hyperlipemia rabbit (see, e.g., tsutsumi etc., 2000, Arzneimittelforschung50 (2): 118-21；Harsch etc., 1998, br j pharmacol124 (2): 227-82； With tanaka etc., 1995, atherosclerosis114 (1): 73-82).
Example for the animal model of people's cancer generally comprises, but is not limited to, the spontaneous tumor producing of companion animals (see, e.g., vail＆macewen, 2000, cancer invest18 (8): 781-92).Animal model for pulmonary carcinoma Example includes, but not limited to lung cancer animal models (1994, in vivo8 (5): 755-69) and the p53 of zhang and roth description The vitiable transgene mouse model of work((see, e.g., morris etc., 1998, j la state med soc150 (4): 179-85).Example for the animal model of mastocarcinoma includes, but not limited to the transgenic of overexpresses cyclin d1 Mice (see, e.g., hosokawa etc., 2001, transgenic res10 (5): 471-8).Animal mould for colon cancer The example of type includes, but not limited to tcr β and p53 double rejecting mice and (see, e.g., kado etc., 2001, cancer res61 (6): 2395-8).Example for the animal model of pancreas cancer includes, but not limited to the cancer of pancreas metastasis model of panc02 mice (see, e.g., wang etc., 2001, int j pancreatol29 (1): 37-46) and the nu-nu for there being subcutaneous pancreatic tumours Mice (see, e.g., ghaneh etc., 2001, gene ther8 (3): 199-208).Dynamic for non_hodgkin lymphoma The example of thing model include, but not limited to severe combined immunodeficiency (" scid ") mice (see, e.g., bryant etc., 2000, lab invest80 (4): 553-73) and ighmu-hox11 transgenic mice (see, e.g., hough etc., 1998, Proc natl acad sci usa95 (23): 13853-8).Example for the animal model of the esophageal carcinoma includes, but does not limit In the transgenic mice for human papillomavirus type 16e7 cancer group (see, e.g., herber etc., 1996, j virol70 (3): 1873-81).Example for the animal model of colorectal carcinoma includes, but not limited to apc mouse model (referring to example As, fodde＆smits, 2001, trends mol med7 (8): 369-73 and kuraguchi etc., 2000, oncogene19 (50): 5755-63).For the animal model of neurofibromatosiss example include, but not limited to be mutated nfl mice (referring to, For example, cichowski etc., 1996, semin cancer biol7 (5): 291-8).For retinoblastoma animal mould The transgenic mice that the example of type includes, but not limited to express simian virus 40t antigen in retina (see, e.g., howes Deng 1994, invest ophthalmol vis sci35 (2): 342-51 and windle etc., 1990, nature343 (6259): 665-9) and inbred rats (see, e.g., nishida etc., 1981, curr eye res1 (1): 53-5 and kobayashi etc., 1982, acta neuropathol (berl) 57 (2-3): 203-8).Example for the animal model of embryoma of kidney includes, but Be not limited to, wt1 reject mice (see, e.g., scharnhorst etc., 1997, cell growth differ8 (2): 133- 43), the rat collateral line (subline) being used for frequently-occurring nephroblastoma (neuphroblastoma) (see, e.g., mesfin And breech, 1996, lab anim sci46 (3): 321-6) and for embryoma of kidney wistar/furth rat (referring to, For example, murphy etc., 1987, anticancer res7 (4b): 717-9).
Example for the animal model of retinitis pigmentosa includes, but not limited to the royal college of Surgeons (" rcs ") rat (see, e.g., vollrath etc., 2001, proc natl acad sci usa98 (22)； 12584-9 and hanitzsch etc., 1998, acta anat (basel) 162 (2-3): 119-26), rhodopsin reject mice (ginseng See, for example, jaissle etc., 2001, invest ophthalmol vis sci42 (2): 506-13) and wag/rij rat (ginseng See, for example, lai etc., 1980, am j pathol98 (1): 281-4).
Example for the animal model of liver cirrhosis includes, but not limited to be exposed to ccl4Rat (see, e.g., Kloehn etc., 2001, horm metab res33 (7): 394-401) and being induced by bacterium or suffering from colitis Rodent model (see, e.g., vierling, 200l, best pract res clin gastroenterol15 (4): 591-610).
Rodent model that the example of haemophiliachemophiliac animal model includes, but not limited to suffer from hemophilia A (referring to, For example, reipert etc., 2000, thromb haemost84 (5): 826-32；Jarvis etc., 1996, thromb haemost75 (2): 318-25；, suffer from the Canis animalss of hemophilia A (referring to example with bi etc., 1995, nat genet10 (1): 119-21) As, gallo-penn etc., 1999, hum gene therl0 (11): 1791-802 and connelly etc., 1998, blood91 (9): 3273-81), suffer from hemophilia b murine animal models (see, e.g., snyder etc., 1999, nat med5 (1): 64- 70；Wang etc., 1997, proc natl acad sci usa94 (21): 11563-6；With fang etc., 1996, gene ther3 (3): 217-22), suffer from hemophilia b rodent model (see, e.g., mount etc., 2002, blood99 (8): 2670- 6)；Snyder etc., 1999, nat med5 (1): 64-70；With fang etc., 1996, gene ther3 (3): 217-22)；And kay Deng 1994, proc natl acad sci usa91 (6): 2353-7) and suffer from hemophilia b macaque macaque model (referring to, For example, lozier etc., 1999, blood93 (6): 1875-81).
For Feng. the example of the animal model of von Willebrand disease includes, but not limited to inbred mouse species Riiis/j (see, e.g., nichols etc., 1994,83 (11): 3225-31 and sweeney etc., 1990,76 (11): 2258- 65), injected botrocetin rat (see, e.g., sanders etc., 1988, lab invest59 (4): 443-52) with for Feng. the pig model of von Willebrand disease (see, e.g., nichols etc., 1995, proc natl Acad sci usa92 (7): 2455-9)；Johnson＆bowie, 1992, j lab clin med120 (4): 553-8) and Brinkhous etc., 1991, mayo clin proc66 (7): 733-42).
Example for the thalassemic animal model of b- includes, but not limited to the Mus for globulin gene mutation Section's model (see, e.g., lewis etc., 1998, blood91 (6): 2152-6)；Raja etc., 1994, br i haematol86 (1): 156-62；Popp etc., 1985,445:432-44；With skow etc., 1983, cell34 (3): 1043-52).
Animal model for renal calculuss includes, but not limited to heritability hypercalcinuria rat and (see, e.g., Bushinsky etc., 1999, kidney int55 (1): 234-43 and bushinsky etc., 1995, kidney int48 (6): 1705-13), chemical-treated rat (see, e.g., grases etc., 1998, scand j urol nephrol32 (4): 261-5；Burgess etc., 1995, urol res23 (4): 239-42；Kumar etc., 1991, j urol146 (5): 1384-9； Okada etc., 1985, hinyokika kiyo31 (4): 565-77；With bluestone etc., 1975, lab invest33 (3): 273-9), hyperoxal-uria rat (see, e.g., jones etc., 1991, j urol145 (4): 868-74), for one side The renograph (see, e.g., seifmah etc., 2001,57 (4): 832-6) of degeneration deformation and block for upper urinary tract Rabbit (see, e.g., itatani etc., 1979, invest urol17 (3): 234-40).
For the animal model of ataxia-telangiectasiss disease example include, but not limited to for ataxia- Telangiectasiss disease murine animal models (see, e.g., barlow etc., 1999, proc natl acad sci usa96 (17): 9915-9 and inoue etc., 1986, cancer res46 (8): 3979-82.
Example for the animal model of lysosomal storage disease includes, but not limited to mucopolysaccharide vii type mouse model (ginseng See, for example, brooks etc., 2002, proc natl acad sci usa.99 (9): 6216-21；Monroy etc., 2002, Bone30 (2): 352-9；Vogler etc., 2001, pediatr dev pathol.4 (5): 42l-33；Vogler etc., 2001, Pediatr res.49 (3): 342-8；, for alochromacy brain white with wolfe etc., 2000, mol ther.2 (6): 552-6) The underfed mouse model of matter (see, e.g., matzner etc., 2002, gene ther.9 (1): 53-63), for Sang De Hough disease mouse model (see, e.g., sango etc., 2002, neuropathol appl neurobiol.28 (1): 23- 34), the mouse model for mucopolysaccharidosises iii a type (see, e.g., bhattacharyya etc., 2001, Glycobiology11 (1): 99-10 and bhaumik etc., 1999, glycobiology9 (12:1389-96), aromatic yl acid ester Enzyme a (asa)-shortage mice (see, e.g., d'hooge etc., 1999, brain res.847 (2): 352-6 and d'hooge etc., 1999, neurosci lett.273 (2) 93-6)；Mice with aspartyl glucose aminuria disease (see, e.g., Jalanko etc., 1998, hum mol genet.7 (2): 265-72)；Feline model (ginseng for mucopolysaccharidosises vi type See, for example, crawley etc., 1998, j clin invest.101 (1): 109-19 and norrdin etc., 1995, bone17 (5): 485-9)；Felid for Niemann's disease c type (see, e.g., march etc., 1997, acta neuropathol (berl) .94 (2): 164-72), ASM lack mice (see, e.g., otterbach＆stoffel, 1995, The cattle of and for reveal glucosides storing up disease (see, e.g., jolly etc., 1975, birth defectss cell81 (7): 1053-6) orig arctic ser.11(6)∶273-8).
Example for the animal model of nodositas sclerencephaly (" tsc ") includes, but not limited to tsc1 mouse model (ginseng See, for example, kwiatkowski etc., 2002, hum mol genet.11 (5): 525-34), tsc1 (tsc1 homologue) reject little Mus (see, e.g., kobayashi etc., 2001, proc natl acad sci usa.2001,7,17；98 (15): 8762- 7), tsc2 gene mutation (eker) rat model (see, e.g., hino2000, nippon rinsho58 (6): 1255-61； Mizuguchi etc., 2000, j neuropathol exp neurol.59 (3): 188-9；With hino etc., 1999, prog exp Tumor res.35:95-108) and tsc2 (+/-) mice (see, e.g., onda etc., 1999, j clin invest.104 (6): 687-95).
4.3 synthesis and preparation
Can through standard, the synthetic method known obtain the compounds of this invention, see, e.g., march, j.advanced organic chemistry；Reactions mechanisms, and structure, fourth edition, 1992.For preparing this The raw material of bright compound and intermediate is commercially available to be buied or can use known synthetic method and reagent to buy raw material system by commercially available Standby.
Synthetic method synthesis type i described in available following scheme a and b or ii compound.The described method system of available lower section Standby the compounds of this invention.
Method formula i compound described in available flow process a.
Flow process a
Commercially available buying, to the unstable resin a1 of acid for example trityl resin, 2- chlorotrityl chloride resin, Phenylacetamidomethyl (pam) resin and p- alkoxybenzyl alcohol resin can be used for the present invention.Different in tertiary amine reagent such as two In the presence of propylethylamine or triethylamine, in suitable solvent such as dichloromethane, dimethylformamide, in toluene, can carry out Benzoic acid compounds a2 and the coupling reaction of trityl resin (x=2- chlorotrityl chloride here).In other method, In the case of diisopropylethylamine in presence or absence of dimethylformamide, using DIC (to benzene Base acetylamino methyl resin and to alkoxybenzyl alcohol resin) or equivalent such as benzotriazole -1- base-epoxide-tripyrrole Alkane-Hexafluorophosphate (pybop), bromo-three-pyrrolidinyl-Hexafluorophosphate (pybrop), 1- ethyl -3- (3- bis- Dimethylaminopropyl) carbodiimide hydrochloride (edc), using standard ester linkage formation conditions it is convenient to prepare acylated resin a3. Can be in atent solvent, such as ethanol, oxolane, dioxane and dimethylformamide or mixed with or without diisopropylethylamine In compound, process the cyanobenzoic ester of resin-combination with azanol, obtain hydrogen-based amidine compound a4.Hydoxyamidine resin a4 can be used as The conventional linker of 1,2,4- diazole series compounds of the various other compounds of structure i shown in synthesis flow a (linker).In the presence of alkaline reagent such as diisopropylethylamine or triethylamine, atent solvent for example dichloromethane, four In hydrogen furan and dimethylformamide or mixture, with reagent a5 (wherein y basis representation leaving group, such as halogeno-group, imidazoles Base, paranitrophenol etc.) make the hydroxyamidines compound acylation of resin-combination.Another alternative approach is, presence or absence of diformazan In the case of diisopropylethylamine in base Methanamide, using DIC or equivalent such as benzotriazole -1- Base-epoxide-three-pyrrolidinyl-Hexafluorophosphate, bromo-three-pyrrolidinyl-rattle hexafluorophosphate, 1- ethyl -3- (3- bis- Dimethylaminopropyl) carbodiimide hydrochloride, easily it is acylated with reagent 5 (wherein group y represents hydroxyl).In acid bar Under part, such as in the presence of 2 molar trifluoroacetic acid in dichloromethane or 3 mole of acetic acid in dichloromethane, crack resin-knot The acylated compounds a6 closing, obtains required compound a7.Be with or without alkaline reagent such as diisopropylethylamine, triethylamine or In the case of triethylammonium tetrakis or tetrabutylammonium fluoride, the ring-closure reaction on free acid compound a7 can be by atent solvent such as first In benzene, oxolane, dioxane and dimethylformamide or its mixture, backflow is carried out, and obtains 1,2,4- diazole compounds i. The dehydrocyclization reaction that the compound a 6 of resin-combination is passed through in another kind of alternative ring-closure reaction carries out (flow process a).This conversion Can be in the case of being with or without alkaline reagent such as triethylamine, diisopropylethylamine or tetrabutylammonium fluoride, in atent solvent For example realize in toluene, oxolane, dioxane and dimethylformamide or its mixture.The temperature of described reaction is in room temperature extremely In the reflow temperature range of solvent.
Above-mentioned solid phase chemistry can be applicable to the liquid phase synthesis of structure i compound.This point is described in below scheme b.
Flow process b
Make cyano compound b1 hydroxyamidines (hydoxyamidinated) with hydroxylamine.This reaction is generally in base reagent example As, in the presence of triethylamine, potassium carbonate or diisopropylethylamine, solvent for example methanol, ethanol, the tert-butyl alcohol, oxolane or Carry out in dimethylformamide, temperature is in the reflow temperature range of room temperature to selected solvent.With reagent b3 (wherein group y table Show some leaving groups, such as halogeno-group, imidazole radicals, paranitrophenol etc. make hydroxyl amidine compound b2 be acylated.Generally in solvent example In dichloromethane, oxolane or dimethylformamide, with alkaline reagent, for example, triethylamine or diisopropylethylamine are carried out Described reaction.In an alternative approach, in the case of being with or without diisopropylethylamine, using DIC or Equivalent such as benzotriazole -1- base-oxo-three-pyrrolidinylHexafluorophosphate, bromo-three-pyrrolidinyl-Hexafluoro Phosphate, 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride, form reaction (wherein y table in common ester bond Show hydroxyl) under it is convenient to carry out acylation reaction.In the feelings being with or without alkaline reagent such as triethylamine or diisopropylethylamine Under condition, solvent such as dichloromethane, oxolane, toluene or dimethylformamide can achieve closing on acylated compounds b4 Ring, temperature can be in the reflow temperature range of room temperature to selected solvent.
4.4 using method
The present invention includes carrying out the disease of reduction of patient by the mrna decay suppressing to translate termination in advance and/or nonsense mediation With the treatment and prevention method of disease, it includes providing the present invention of therapeutically effective amount to the patient of the such treatment of needs or prevention Compound or its pharmaceutically acceptable prodrug, solvate, metabolite, polymorph, salt, solvate, hydrate or bag Compound.
In one embodiment, the present invention includes declining with the mrna showing translation termination in advance and/or nonsense mediation The relevant treatment of any disease of gene becoming or prevention.In one embodiment, described diseased portion ground is by from advance Caused by the shortage of the expression of the gene of termination codon.Show the mrna decay that translation terminates in advance and/or nonsense mediates Gene and terminate in advance with translation and/or the instantiation of the relevant disease of mrna decay of nonsense mediation sees 2002 6 The U.S. Patent Application No. 60/390,747 that the moon 21 was submitted to, entitled: to adjust translation and terminate in advance declining with the mrna of nonsense mediation The discrimination method of the small molecule becoming, is attached to herein by reference of text.
It is translated and terminate in advance and/or the disease alleviated of suppression of mrna decay of nonsense mediation includes, but are not limited to: Heredopathia, cancer, autoimmune disease, hematopathy, collagen, diabetes, neurodegenerative disease, proliferative disease, the heart Angiopathy, pneumonopathy, inflammatory diseasess or central nervous system disease.
Concrete genetic diseasess in the range of the inventive method include, but not limited to amyloidosis, hemophilia, Ah Er Cihai Mo's disease, tay sachs disease, atherosclerosiss, giantism, dwarfism, hypothyroidism, thyroid machine Can hyperfunction, aging, obesity, parkinson, Niemann's disease, cystic fibrosises, muscular dystrophy, heart disease, renal calculuss, altogether Ji imbalance-telangiectasia, familial hypercholesterolemia, retinitis pigmentosa, lysosomal storage disease, nodositas are hard Change, duchenne muscular dystrophy and Marfan's syndrome.Entity tumor and other cancer are included in the method for the present invention.
In another embodiment, described heredopathia is autoimmune disease.In preferred embodiments, described itself Immune disease is rheumatoid arthritiss or graft versus host disease.
In another embodiment, described heredopathia is hematopathy.In preferred embodiments, described hematopathy is blood friend Disease, Feng. von Willebrand disease, asynergy-capillary dilation, b- thalassemia or renal calculuss.
In another embodiment, described genetic diseasess are collagen.In one embodiment, described collagen is skeletonization Complete or liver cirrhosis.
In another embodiment, described genetic diseasess are diabetes.
In another embodiment, described genetic diseasess are inflammatory diseasess.In a preferred embodiment, described inflammatory disease Disease is arthritis.
In another embodiment, described genetic diseasess are central nervous system disease.In one embodiment, described Central nervous system disease is neurodegenerative disease.In a preferred embodiment, described central nervous system disease is many The property sent out hardening, muscular dystrophy, duchenne muscular dystrophy, Alzheimer, tay sachs disease, infantile neuronal Ceroid lipofuscinosis (lincl) or parkinson.
In another embodiment, described genetic diseasess are cancers.In a preferred embodiment, described cancer is Head cancer and neck cancer, cancer eye, skin carcinoma, oral cancer, laryngeal carcinoma, esophageal carcinoma, breast cancer, osteocarcinoma, pulmonary carcinoma, colon cancer, carcinomaofsigmoid, straight Intestinal cancer, gastric cancer, carcinoma of prostate, mastocarcinoma, ovarian cancer, renal carcinoma, hepatocarcinoma, pancreas cancer, the brain cancer, intestinal cancer, heart cancer or adrenal carcinoma.
In another preferred embodiment of the present, described cancer is relevant with tumor suppressor gene (see, e.g., garinis etc. 2002, hum gen111: 115-117；1998, proc.natl.acad.sci.usa, the 95:15587-15591 such as meyers； 2000, the nature medicine6 such as kung (12): 1335-1340).This kind of tumor suppressor gene include, but not limited to apc, Atm, brac1, brac2, msh1, pten, rb and p53.
In particularly preferred embodiments, described tumor suppressor gene is p53 gene.In p53, identify nonsense Mutation is it is meant that nonsense mutation is relevant with cancer.Several nonsense mutations having identified in p53 gene (see, e.g., Masuda etc., 2000, tokai j exp clin med.25 (2): 69-77；Oh etc., 2000, mol cells10 (3): 275- 80；Li etc., 2000, lab invest.80 (4): 493-9；Yang etc., 1999, zhonghua zhong liu za zhi21 (2): 114-8；Finkelstein etc., 1998, mol diagn.3 (1): 37-41；Kajiyama etc., 1998, dis Esophagus.11 (4): 279-83；Kawamura etc., 1999, leuk res.23 (2): 115-26；Radig etc., 1998, hum pathol.29(11)∶1310-6；Schuyer etc., 1998, int j cancer76 (3): 299-303；Wang-gohrke etc., 1998, oncol rep.5 (1): 65-8；Fulop etc., 1998, j reprod med.43 (2): 119-27；Ninomiya etc., 1997, j dermatol sci.14 (3): 173-8；Hsieh etc., 1996, cancer lett.100 (1-2): 107-13；rall Deng 1996, pancreas.12 (1): 10-7；Fukutomi etc., 1995, nippon rinsho.53 (11): 2764-8； Frebourg etc., 1995, am j hum genet.56 (3): 608-15；Dove etc., 1995, cancer surv.25:335- 55；Adamsom etc., 1995, br j haematol.89 (1): 61-6；Grayson etc., 1994, am j pediatr Hematol oncol.16 (4): 341-7；Lepelley etc., 1994, leukemia.8 (8): 1342-9；Mcintyre etc., 1994, j clin oncol.12 (5): 925-30；Horio etc., 1994, oncogene.9 (4): 1231-5；Nakamura etc., 1992, jpn j cancer res.83 (12): 1293-8；Davidoff etc., 1992, oncogene.7 (1): 127-33；With Ishioka etc., 1991, biochem biophys res commun.177 (3): 901-6；These disclosures are incorporated by reference into Herein).Without being bound by any theory of these mrna decays that compound mediated translation terminates in advance and/or nonsense mediates, can With formula i or ii compounds for treating or prevention, any disease relevant with the p53 gene of coding premature translation codon includes, but It is not limited to, the nonsense mutation described in previously cited list of references.
In other embodiments, by giving the formula i compounds for treating of patient in need's effective dose or prevention Disease includes: entity tumor, sarcoma, cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, notochord Tumor, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma, synovioma, mesothelioma, Ewing's sarcoma, smooth muscle Sarcoma, rhabdomyosarcoma, colon tumor, pancreas cancer, mastocarcinoma, ovarian cancer, carcinoma of prostate, squamous cell carcinoma, basal cell carcinoma, gland Cancer, syringocarcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, bone marrow cancer, bronchogenic carcinoma, renal cell carcinoma, hepatocyte Tumor, cancer of biliary duct, choriocarcinoma, spermocytoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, pulmonary carcinoma, minicell Pulmonary carcinoma, bladder tumor, epithelioma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, card Ripple Ji sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, one-tenth Neurocytoma, retinoblastoma, hemopoiesis tumor, acute lymphoblastic leukemia, acute lymphoblast b cell are white Disorders of blood, acute lymphoblast t chronic myeloid leukemia, acute myeloblastic leukemia, acute promyelocitic leukemia, acute monokaryon Chronic myeloid leukemia, Di Guglielmo syndrome, acute megakaryocytic leukemia, Acute Meyloid monocytic leukemia, acute non-lymph Chronic myeloid leukemia, acute undifferentiated cell leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hair cell are white Disorders of blood or multiple myeloma.See, e.g., harrison ' s principles of internal medicine, Eugene braunwald etc. edits, the 491-762 page (the 15th edition, 2001).
In preferred embodiments, the present invention includes treating or prevent adjusted translation to terminate in advance and/or nonsense mediation Mrna decay and the disease alleviated, or the method alleviating one or more symptom relevant with this, the method includes with effective Formula i of amount or ii compound exposing cell.The cell that the inventive method is comprised includes zooblast, mammalian cell, thin The cell of bacterium cell, plant cell and virus infection.In one embodiment, nonsense codon is present in for generations in dna.? In another embodiment, described nonsense codon predisposition becomes generation.
In certain embodiments, as the disease that the mrna decay terminating in advance with translation and/or nonsense mediates is relevant Preventive measure, give patient, preferably mammal, more preferably people, formula i or ii compound or its pharmaceutically acceptable salt.
In a preferred embodiment, first confirm that the mrna that patient suffers from and translates termination in advance and/or nonsense mediation Decay relevant disease.In another embodiment, by acceptable nonsense mutation screening test, described patient is through screening There is nonsense mutation to determine in process, this process includes the step screening patient or the cell therefrom extracting.In the side of being preferable to carry out In case, the dna of described patient can be sequenced or accept southern blot, polymerase chain reaction (pcr), short file repetition sequence The use of row (short tandem repeat) (str) or polymorphic length restriction fragment (rflp) analysis, to confirm described trouble Whether there is nonsense mutation in the dna of person.In addition, through Western blot or other immunity test, as the albumen containing nonsense mutation Change horizontal expression in patient, can confirm that nonsense mutation.In another embodiment, described patient is unborn fetus, The screening of the presence through intrauterine nonsense mutation for the fetus.Can before birth or birth after giving construction i or ii compound.? In related embodiment, described treatment is embodied in, described patient through nonsense mutation screening test, and through giving one or more The compounds of this invention is treated；Especially, with being particularly suitable for the patient described in compounds for treating of described mutation；For example according to described The type of disease, cell type and described gene.This kind of method is well known to those skilled in the art.
In another embodiment, terminate in advance for translation and/or nonsense mediation mrna decays, use-case such as said method (i.e. the dna of cell can be sequenced or accept southern blot, polymerase chain reaction (pcr), short Tandem Repeat (str) Using or polymorphic length restriction fragment (rflp) analysis, to confirm to whether there is nonsense mutation in the dna of described cell) sieve Select described cell (for example, zooblast, mammalian cell, cell, plant cell and virus infected cell).
The concrete grammar of the present invention, also includes giving of other therapeutic agents (not being the therapeutic agent of the compounds of this invention). In certain embodiments of the invention, the compound of the present invention can be used with least one other therapeutic agent.Therapeutic agent Include, but not limited to Nonopioids；Nonsteriodal anti-inflammatory；Bendectin；Beta-adrenergic blockade medicine；Convulsion Medicine antidepressants；ca2+- carrier frequency channel break medicine；Anticarcinogen and its mixture.
In certain embodiments, formula i or ii compound can be with anticarcinogen administering drug combinations or preparations.Applicable anticancer medicated bag Include, but be not limited to, alkyl chemical medicine；Nitrogen is situated between；Folate antagonist；Purine antagonist；Pyrimidine antagonists；Spindle poisonous substance；Topology Isomerase inhibitors；Apoptosis inducing agents；Angiogenesis inhibitor；Podophyllotoxin；Nitroso ureas；Cisplatin；Carboplatin；Interference Element；Asparaginase；Tamoxifen；Leuproside；Flutamide；Megestrol；Mitomycin；Bleomycin；Doxorubicin；She Stand and replace health and Taxol.
In certain embodiments, formula i or ii compound can be with Antibiotic combination administration or preparations.In some embodiments In, described antibiotic is macrolide (for example, tobramycin), cephalosporinses (for example, CefalexinCefradineCefuroximeCefprozilCefaclorCefiximeOr cefadroxilClarithromycin (for example, clarithromycinErythromycin (for example, erythromycinPenicillin (for example, penicillin v (Or)) or quinolinoness (for example, OfloxacinCiprofloxacinOr norfloxacinIn preferred embodiments, described antibiotics against P pseudomonas (pseudomonas aeruginosa) Active.
The compound of the present invention and other medicines can play superposition or more preferably synergism.Preferably real at one Apply in scheme, the compositionss containing the compounds of this invention and partly identical or different with compositionss containing the compounds of this invention compositionss Another kind of medicine be administered simultaneously.In another embodiment, the compounds of this invention is before another kind of medicine is administered Or after give.
However, in the treatment of acute or chronic disease or disease, the prevention of concrete activity composition of the present invention or treatment The amplitude of dosage can be different with the route of administration of the property of described disease or disease and seriousness and described active component.Institute State dosage and may is that times for spraying also can be different according to the age of concrete patient, body weight and response.With due regard to these because Element, the readily selected applicable dosage of those skilled in the art.Usually, as single dose once a day, preferably It is administered with divided dose in one day, the recommended scope of disease described herein is between daily about 0.1mg- about 2000mg scope Interior.In one embodiment, give daily dose with single dose or decile dosage.Particularly, daily dose scope should be from every Its about 5mg-500mg, more particularly between daily about 10mg- about 200mg.During treatment patient, the entirety depending on described patient is rung Should, treatment should be from the beginning of low dosage, as single dose or separate doses, perhaps daily about 1mg- about 25mg, and if necessary When increase to up to about 200mg- about 2000mg.
In some cases, the using dosage of described active component is it may be necessary to exceed scope disclosed herein, this It is obvious to those of ordinary skill in the art.Moreover, it is to noticed that according to the response of concrete patient, clinician or internal medicine Doctor can understand how and when stop, adjusts or terminate to cure.
Phrase " therapeutically effective amount " for this paper, " prevention effective dose " and " treatment or prevention effective dose ", including above-mentioned Dosage and administration number of times plan.Different therapeutically effective amounts is applicable to different diseases and disease, and this is easy to general for this area Logical technical staff is understood.Similarly it is sufficient to treating or preventing this kind of disease, but it is not enough to produce, or enough to reduce and routine The amount of the side effect of therapy-related, is also included within above-mentioned dosage and administration number of times in the works.
4.5 Pharmaceutical composition
Containing the compounds of this invention or its pharmaceutically acceptable polymorph, prodrug, salt, solvate, hydrate or The Pharmaceutical composition of clathrate and single unit dosage forms are also included in the present invention.The concrete dosage form of the present invention is applicable to mouth Clothes, mucosa (including Sublingual, oral cavity, rectum, nose or vagina), parenteral (include subcutaneous, intramuscular, large bolus injection, intra-arterial or Intravenouss), transdermal or local be administered.
The Pharmaceutical composition of the present invention and dosage form comprise the compounds of this invention or its pharmaceutically acceptable prodrug, polymorphic Thing, salt, solvate, hydrate or clathrate.The Pharmaceutical composition of the present invention and dosage form generally comprise one or more pharmacy Upper acceptable excipient.
Concrete Pharmaceutical composition included by this embodiment comprises the compounds of this invention or it is pharmaceutically acceptable many Crystal formation thing, prodrug, salt, solvate, hydrate or clathrate, and at least one other medicine.Other medicines Example includes, but are not limited to: cancer therapy drug and anti-inflammatory drug, including but not limited to, those described in 4.3 sections above.
The single unit dosage forms of the present invention be applied to patient be administered orally, mucosa (such as nose, Sublingual, vagina, oral cavity or rectum), Parenteral (for example subcutaneous, intravenouss, large bolus injection, intramuscular or intra-arterial) or transdermal administration.The example of dosage form includes, but not It is limited to: tablet, Caplet；Capsule, for example, soft elastic gelatin capsule；Cachet；Dragee；Lozenge；Dispersant；Suppository； Ointment；Paste (paste)；Paste；Powder；Dressings；Cream；Plaster；Solution；Patch；Aerosol (for example, nose spray Mist agent or inhalant)；Gel；Be applied to patient be administered orally or mucosa delivery liquid dosage form, including suspension (for example, aqueous or Not liquid, aqueous suspension, oil-in-water emulsion or water-in-oil emulsion), solution and elixir；It is applied to the liquid of patient's parenteral Dosage form；With restructural to be applied to sterilizing solid (for example, crystal formation or the amorphous of the liquid dosage form providing parenteral to patient Type solid).
The compositionss of the present invention, the shape of dosage form and type typically change with its purposes.For example, with for same disease The dosage form of chronic treatment compare, for inflammation or the acute treatment of relevant disease dosage form can contain more substantial included by it One or more active component.Similarly, compared with for treating the peroral dosage form of same disease and disease, parenteral dosage form Its one or more contained active component lesser amount of can be contained.These and other shape of concrete dosage form included by the present invention Formula can be mutually different, and this is obvious to those skilled in the art.See, e.g., remington ' s Pharmaceutical sciences, the 18th edition, mack publishing, easton pa (1990).
General Pharmaceutical composition and dosage form contain one or more carrier, excipient or diluent.Applicable excipient Known to the technical staff of pharmaceutical field, provided herein is the non-limiting examples of the excipient being suitable for.Or concrete excipient It is suitable for incorporation in Pharmaceutical composition, or dosage form depends on various factors known in the art, including but not limited to, institute State the presentation mode to patient for the dosage form.For example, peroral dosage form such as tablet can contain the tax not being suitable for parenteral dosage forms Shape agent.The suitability of concrete excipient also may depend on the concrete activity composition in described dosage form.
Because water can promote the degraded of some compounds, present invention additionally comprises the anhydrous pharmaceutical composition containing active component And dosage form.For example, pharmaceutical field accepts extensively the method as the long-term storage of simulation for the addition (for example, 5%) of water, to confirm to make The stability of the property of agent such as shelf life or over time.See, e.g., jens t.carstensen, drug Stability.principles ＆ practice, the second edition, marcel dekker, ny, ny, 1995, the 379-80 page.Thing In reality, the decomposition of some compounds of water and thermal acceleration.Therefore, because the preparation of preparation, processing, packing, store, ship and making With during often touch moisture content and/or dampness, water can be extremely significant to the effect of preparation.
Under conditions of low moisture content or low humidity, with containing anhydrous or contain low-moisture various composition, can prepare the present invention's Anhydrous pharmaceutical composition and dosage form.If substantial contact with moisture and/or dampness are it is desirable to contain during preparation, packaging and/or storage There are Lactose and the Pharmaceutical composition of at least one active component (containing primary amine or secondary amine) and dosage form preferably anhydrous.
For keeping no aqueouss, should prepare and store anhydrous pharmaceutical composition.It is therefore preferable that preventing from being exposed to water with known Anhydrous composition packed by material, so that they can be packaged in the kit of applicable regulation.The example of applicable packaging includes But it is not limited to the tinfoil of air-locked sealing, plastics, unit-dose container (for example, bottle), blister gentle bag dress.
Present invention additionally comprises containing reduce active ingredient breaks down speed the Pharmaceutical composition of one or more compound and Dosage form.This kind of compound of referred to herein as " stabilizer " includes, but not limited to antioxidant such as ascorbic acid, ph buffering Agent or salt buffer agent.
As the quantity of excipient is the same with type, in dosage form the quantity of active component and particular type can according to for example, but It is not limited to, different to the factor of the approach of patient's administration.However, as single dose once a day in the morning, preferably one Natural gift are taken with food for several times simultaneously, containing the compounds of this invention or its pharmaceutically acceptable salt, solvate, clathrate, The exemplary dosage form of the present invention of hydrate, polymorph or prodrug is in the range of daily about 0.1mg- about 2000mg.More specifically Ground says, daily dose is taken twice daily with decile dosage.Specifically, daily dose scope should be daily about 5mg- about 500mg, More specifically, between daily about 10mg- about 200mg.During treatment patient, depending on the Whole Response of described patient, treatment should be from Low dosage starts, as single dose or separate doses, perhaps daily about 1mg- about 25mg, if desired for when increase to daily up to About 200mg- about 2000mg.
4.5.1 peroral dosage form
The Pharmaceutical composition being applied to the oral present invention can be in discrete dosage forms, (for example may be used such as, but not limited to, tablet Chewable tablet), Caplet, capsule and liquid (syrup that for example, taste masking is crossed).This kind of dosage form contains the activity one-tenth of scheduled volume Point, and available method of pharmacy preparation well known to the skilled artisan in the art.Referring generally to remington ' s Pharmaceutical sciences, the 18th edition, mack publishing, easton pa (1990).
According to conventional manner hybrid technology, closely mixed with least one excipient by making described active component, preparation The general peroral dosage form of the present invention.According to the dosage form of desired route of administration, excipient can take many forms.For example, fit For liquid oral or aerosol dosage forms excipient include, but not limited to water, glycol, oil, alcohol, flavour enhancer, preservative and Toner.The example being applied to the excipient of solid oral dosage form (for example, powder, tablet, capsule and Caplet) includes, but It is not limited to, starch, sugar, Microcrystalline Cellulose, diluent, granulating agent, lubricant, binding agent and disintegrating agent.
The liquid preparation of oral administration can be taken, for example, the form of solution, syrup or suspension, or they are before use It is in the dried product form that water to be used or other are suitable for solvent preparation.Available conventional method, uses pharmaceutically acceptable interpolation Agent such as suspending agent (for example, sorbitol syrups, cellulose derivative or hydrogenated edible fats)；Emulsifying agent (for example, lecithin Or arabic gum)；Non-aqueous solvent (for example, the vegetable oil of almond oil, grease, ethanol or fractional distillation)；With preservative (for example, first Base or propyl group-p-Hydroxybenzoate or sorbic acid) prepare this kind of liquid preparation.When needing, described preparation also can contain buffering Salt, correctivess, coloring agent and sweeting agent.
It is administered because it is convenient, tablet and the favourable oral dosage unit form of Capsules representative, use solid in these situations Body excipient.If desired, available standards aqueous or not aqueous techniques are to tablet coating.Any method of pharmacy is can use to prepare this kind of Dosage form.In general, by make described active component and liquid-carrier, finely divided solid carrier or both uniformly and closely mix Close, if desired for the form of expression required for making product become again, prepare Pharmaceutical composition and dosage form.
For example, can suppress or mould piece agent.Can in applicable machine, suppress in free-flowing form such as powder or Granule, the optional active component mixing with excipient, prepares compressed tablets.In applicable machine, by making in powder , the mixture of the compound being moistened with inert liquid diluent molded, molded tablet can be prepared.
The example that can be used for the excipient of peroral dosage form of the present invention includes, but not limited to binding agent, filler, disintegrating agent And lubricant.Binding agent be applied to Pharmaceutical composition and dosage form include, but not limited to corn starch, potato starch or Other starch, gelatin, natural and synthesis natural gum for example arabic gum, sodium alginate, alginic acid, other alginate, powdered tragacanth, (for example, ethyl cellulose, cellulose ethanoate, carboxymethylcellulose calcium, carboxymethyl are fine for guar gum, cellulose and its derivates The plain sodium of dimension), polyvinyl pyrrolidone, methylcellulose, Pregelatinized Starch, HYDROXY PROPYL METHYLCELLULOSE (for example, the 2208th, 2906, No. 2910), Microcrystalline Cellulose and its mixture.
(for example, the example of the filler be applied to Pharmaceutical composition and dosage form includes, but not limited to Talcum, Calcium Carbonate Granule or powder), Microcrystalline Cellulose, cellulose powder, dextratess, kaolin, xylitol, silicic acid, Sorbitol, shallow lake Powder, Pregelatinized Starch and its mixture.Binding agent in Pharmaceutical composition of the present invention or filler are typically with described pharmaceutical compositions About 50- about 99% weight of thing and dosage form exists.
The service form of Microcrystalline Cellulose include, but not limited to avicel-ph-101, avicel-ph-103, The raw material that avicel rc-581, avicel-ph-105 sell is (from fmc corporation, american viscose Division, avicel sales, marcus hook, pa buy) and its mixture.Concrete binding agent is with avicel rc- 581 sales, the mixture of Microcrystalline Cellulose and sodium carboxymethyl cellulose.Applicable anhydrous or low moisture excipients or additive Including avicel-ph-103tmWith starch (starch) 1500lm.
For making tablet disintegrate when being exposed to aqueous environment, disintegrating agent can be adopted in the present compositions.Containing too many The meeting disintegrate in storage of the tablet of disintegrating agent, and those tablets containing disintegrating agent very little can not be with the speed of needs or desired Under the conditions of disintegrate.Therefore it should with enough (both not many and not very little so that adversely in described active component discharge) Disintegrating agent formed the present invention solid oral dosage form.According to the type of preparation, the amount of disintegrating agent used is different, and this is to ability The those of ordinary skill in domain is easily recognizable.General Pharmaceutical composition contains the disintegrating agent of about 0.5- about 15% weight, special It is not the disintegrating agent of about 1- about 5% weight.
The disintegrating agent of the Pharmaceutical composition and dosage form that can be used for the present invention include, but not limited to agar, alginic acid, Calcium Carbonate, Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, polacrilin potassium, sodium starch glycolate, Ma Ling Potato or tapioca, Pregelatinized Starch, other starch, clay, other sodium alginate (algins), other cellulose, natural gum and its Mixture.
The lubricant of the Pharmaceutical composition and dosage form that can be used for the present invention includes, but not limited to calcium stearate, stearic acid Magnesium, mineral oil, light mineral oil, glycerol, Sorbitol, xylitol, Polyethylene Glycol, other glycol, stearic acid, lauryl sulfate Sodium, Talcum, hydrogenated vegetable oil (for example, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, sunflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil), hard Fat acid zinc, ethyl oleate, ethyl laurate, agar and its mixture.Other lubricants include, for example, syloid silica gel (aerosil200, by w.r grace co.of baltimore, prepared by md), synthesized silicon rubber solidification aerosol (by plano, The degussa co. of tx sells), cab-o-sil (by boston, the pyrogenic silica product that the cabot co. of ma sells) And its mixture.If it is desired that with lubricator, typically with about 1% weight less than their Pharmaceutical compositions to be incorporated into or dosage form Amount use.
4.5.2 controlled release form
Available controlled fashion or the active component of the transfer device offer present invention, this is those of ordinary skill in the art institute Know.Example includes, but not limited to U.S. Patent number: 3,845,770,3,916,899,3,536,809,3,598,123 and 4, 008,719、5,674,533、5,059,595、5,591,767、5,120,548、5,073,543、5,639,476、5,354,556 With 5, those described in 733,566, it is incorporated herein in by quoting each of which.By adopting, for example, hydroxypropyl methyl is fine Tie up plain, other polymer raw materials, gel, permeable membrane, osmosis system, multiple coatings, microgranule, liposome, microsphere or they Combination, the release mode of the different proportion required for providing, this kind of dosage form can be used to provide the slow of one or more active component Slow or control release.Applicable controlled release preparation containing inventive compound known to persons of ordinary skill in the art (includes this Those described in literary composition) it is readily able to select use.Therefore, the present invention includes the single unit dosage forms example being applied to oral administration As, but be not limited to, it is suitable to tablet, capsule, soft capsule and the Caplet of controlled release.
All controlled release medicines have a common target: make the similar drugs institute that curative effect of medication is increased to exceed non-controlled release The curative effect reaching.It is desirable that in drug treatment, the handling characteristicss of the controlled release preparation of optimal design are, with minimum medicine Thing was treated or symptom management within the time the shortest.The advantage of controlled release preparation includes extending the activity of described medicine, reduces medication Number of times, increases the compliance of patient.Additionally, controlled release preparation is also used for affecting the onset time of medicine or other characteristic, such as institute State the blood level of medicine, thus the generation of secondary (being for example harmful to) effect can be affected.
Most controlled release preparation is designed to initially discharge a certain amount of medicine (active component), promptly produces required Therapeutic effect, then extend time in, gradually and continually discharge the medicine of its surplus, with maintain this treatment or prevent Level.In order to maintain this constant levels of drugs in vivo it is necessary to discharge described from described dosage form with certain speed Medicine, this can supplement from the medication amount being metabolized in vivo and drain.Can use various conditions, including but not limited to, ph, temperature, enzyme, Water or other physiological conditions or compound, the controlled release of stimulating activity composition.
4.5.3 parenteral dosage form
Can be through number of ways, including but not limited to, subcutaneous, intravenouss (inclusion large bolus injection), intramuscular and intra-arterial, to Patient provides parenteral dosage form.Because their administration typically bypasses the natural preventive to pollutant for the patient, parenteral agent Type is preferably sterilizing or can sterilizing before providing to patient.The example of parenteral dosage form includes, but not limited to be injected Solution, dry productss to be dissolved or being suspended in pharmaceutically acceptable injection solvent, suspension to be injected and emulsion.
The applicable solvent that can be used to prepare parenteral dosage form of the present invention is well known for ordinary skill in the art.Example Include, but not limited to usp injection water；Aqueous vehicle is such as, but not limited to, sodium chloride injection, ringer's solution, glucose note Penetrate liquid, dextrose ＆ sodium chloride injection and Lactated Ringer'S Solution；Water-soluble solvent, such as, but not limited to, ethanol, gathers Ethylene glycol and polypropylene glycol；Aqueous vehicle is not such as, but not limited to, Semen Maydis oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum sesami, Oleic acid second Ester, isopropyl myristate and Benzyl Benzoate base ester.
The compound improving the dissolubility of one or more active component disclosed herein may also incorporated into the present invention's In parenteral dosage form.
4.5.4 transdermal and topical formulations
The transdermal of the present invention and topical formulations include, but not limited to cream, lotion, ointment, gel, solution, breast Agent, suspension agent or other forms known to those of skill in the art.See, e.g., remington ' s Pharmaceutical sciences, the 18th edition, mack publishing, easton pa (1990)；And introduction To pharmaceutical dosage forms, the 4th edition, lea＆febiger, philadelphia (1985).Transdermal dosage form Including " reservoir devices " or " matrix (matrix) type " patch, it can be attached on skin, and sticks a period of time to permeate requirement Active component.
For providing the applicable excipient (for example, carrier and diluent) of transdermal included by the present invention and topical formulations Known to the technical staff being pharmaceutical field with other raw materials and to be applied depending on given Pharmaceutical composition or dosage form Concrete tissue.In view of the nontoxic and pharmaceutically acceptable fact, typical excipient includes, but not limited to water, acetone, second Alcohol, ethylene glycol, polypropylene glycol, 1,3 butylene glycol, isopropyl myristate, isopropyl palmitate, mineral oil and its mixture, with Form lotion, tincture, cream, Emulsion, gel or ointment.If desired, also humidizer or wetting agent can be added to this In bright Pharmaceutical composition or dosage form.The example of this kind of adding ingredient is known in the art.See, e.g., remington ' s Pharmaceutical sciences, the 18th edition, mack publishing, easton pa (1990).
Depending on concrete tissue to be treated, can be before the active treatments with the present invention, use simultaneously or after Other components.For example, penetration enhancer can be used to help described active component to be delivered to described tissue.Applicable penetration enhancer Include, but are not limited to: acetone；Various alcohol such as ethanol, oleyl alcohol and oxolane alcohol；Alkyl sulfoxide such as dimethyl sulfoxide；Diformazan Yl acetamide；Dimethylformamide；Polyethylene Glycol；Ketopyrrolidine such as polyvinyl pyrrolidone；Kollidon level (polyethylene Ketopyrrolidine, polyvidone)；Carbamide；With various solvable or water-fast sugar ester such as tween 80 (polyoxyethylene sorbitan monoleate) and department Disk -60 (monoester Pyrusussuriensiss are smooth).
Also the ph of scalable Pharmaceutical composition or dosage form or described Pharmaceutical composition or dosage form tissue to be applied, to promote The transmission of one or more composition.Similarly, the polarity of scalable solvent carrier, its ionic strength or ionic with promote pass Pass.Also compound such as stearate can be added in Pharmaceutical composition or dosage form, to beneficially modify one or more activity The hydrophilic of composition or lipophile, faciliated diffusion.Therefore, stearate can be used as the Lipid carrierses of described preparation, as emulsifying Agent or surfactant and transmission promote or penetration enhancer.The different salt of described active component, hydrate or solvate Can be used to adjust the property of generated compositionss further.
4.5.5 transmucosal dosage forms
The transmucosal dosage forms of the present invention include, but not limited to the technology of ophthalmic solution, spray and aerosol or this area Other forms known to personnel.See, e.g., remington ' s pharmaceutical sciences, the 18th edition, mack Publishing, easton pa (1990)；With introduction to pharmaceutical dosage forms, the 4th Version, lea＆febiger, philadelphia (1985).The dosage form being applied to the mucous tissue in treatment oral cavity can be configured to gargle Agent or buccal cavity gel agent.In one embodiment, described aerosol contains carrier.In another embodiment, described gas Colloidal sol carrier-free.
By suck also can directly to lung giving construction i or ii compound (see, e.g., tong etc., pct application, Wo97/39745；Clark etc., pct apply for, wo99/47196, and it is incorporated herein by reference).For inhalation, use The compound of formula i or ii easily can be delivered to lung by different devices in a large number.For example, the low boiling containing being suitable for is can be utilized to push away Enter agent, such as dichlorodifluoromethane, Arcton 11, the pressurized canister of dichlorotetra-fluoroethane, carbon dioxide or other suitable gas (canisters) metered amount inhaler (" mdi ") is directly to lung delivery type i compound.Can be to many suppliers such as 3m corporation、aventis、boehringer ingleheim、forest laboratories、glaxo-wellcome、 Schering plough and vectura buys mdi device.
In addition, available Diskuses (dpi) device to lung giving construction i compound (see, e.g., raleigh etc., Proc.amer.assoc.cancer research annual meeting, 1999,40,397, it is incorporated by reference into this In literary composition).Dpi device is general to adopt the dry powder cloud for example producing in the outburst of container internal gas, then the machine being inhaled by a patient Reason.Dpi device also be known in the art, can include to many retailers, for example, fisons, glaxo-wellcome, Inhale therapeutic systems, ml laboratories, qdose and vectura buy.The change of popularization is many Dosage dpi (" mddpi ") system, it can transmit more than one therapeutic dose.Can be to such as astrazeneca, glaxo Wellcome, ivax, schering plough, skyepharma and vectura buy mddpi device.For example, use can be prepared In gelatine capsule and the cartridge case of inhaler or insufflator, wherein contain described compound and the powdered substrate being applied to these systems The mixture of powders of such as Lactose or starch.
Can be used for the another type of device of lung delivery type i or ii compound is by such as aradigm The liquid dispensing apparatus that corporation provides.Liquid spray systems make liquid pharmaceutical formulation aerosol using minimum nozzle bore Change, so that intrapulmonary can be directly sucked in.
In preferred embodiments, with atomizer arrangement to lung delivery type i or ii compound.By using for example, super The fine grained that acoustic wave energy generation is easily absorbed, liquid pharmaceutical formulation can be generated aerosol and (see, e.g., by nebulizer Verschoyle etc., british j cancer, 1990,80, suppl2,96, it is incorporated herein by reference).Atomization The example of device includes that (referring to, armer etc., the U.S. is special by sheffield/systemic pulmonary delivery ltd. Profit the 5,954,047th；Van der linden etc., U.S. Patent No. 5,950, No. 619；Van der linden etc., the U.S. Patent the 5,970,974th；Be bonded to herein by quoting), aventis and batelle pulmonary The device that therapeutics provides.Currently study with transmitting through the atomizer arrangement and formula i compounds for treating of suction Air flue digestive tract cancer (aerodigestive cancer) (engelke etc., poster342at american association Of cancer research, san francisco, calif., April 1-5,2000) and pulmonary carcinoma (dahl etc., poster524at American association of cancer research, san francisco, calif., April 1-5,2000).
In particularly preferred embodiments, electricity consumption hydromechanical (" ehd ") aerosol device is to lung delivery type i or ii Compound.Ehd aerosol device electric energy makes liquid agent solution or suspension aerosolization (see, e.g., noakes etc., the U.S. The patent No. 4,765,539；Coffee, U.S. Patent number 4,962,885；Coffee, pct apply for, wo94/12285；Coffee, Pct applies for, wo94/14543；Coffee, pct apply for, wo95/26234；Coffee, pct apply for, wo95/26235； Coffee, pct apply for, wo95/32807, and it is incorporated herein by reference).Should when being transmitted to lung with ehd aerosol device During medicine, the electrochemical properties of the preparation of formula i compound can be the important parameter optimizing, and those skilled in the art can be conventional Carry out this kind of optimization.Compared with existing lung Transfer Technology, ehd aerosol device more effectively can transmit medicine to lung.Formula i or iiization Other methods of the intrapulmonary transmission of compound are also known to those skilled in the art, and within the scope of the invention.
It is applied to and generally comprise formula iization with the liquid pharmaceutical formulation of nebulizer, liquid dispensing apparatus and ehd aerosol device Compound and pharmaceutically acceptable carrier.Described pharmaceutically acceptable carrier be preferably liquid for example alcohol, water, Polyethylene Glycol or Perfluocarbon.Another kind of raw material can be optionally added to change formula i or the solution of ii compound or the Aerosol Properties of suspension.Described Raw material is preferably liquid such as alcohol, glycol, polyglycols or fatty acid.It will be apparent to one skilled in the art that be applied to using aerosol device Liquid agent solution or other compound methods of suspension (see, e.g., biesalski, U.S. Patent number 5,112,598； Biesalski, 5,556,611, incorporated herein by reference).Also formula i compound can be configured to rectum or vagina combination Thing, the such as suppository containing conventional suppository bases such as cocoa butter or other glyceride or retention enema.
In addition to above-mentioned preparation, formula i or ii compound also can be formulated into reservoir (depot) preparation.This kind of long-acting reservoir system Agent can implanted (for example, subcutaneously or intramuscularly) or through intramuscular administration.Thus, for example, can use suitable macromolecular material or Hydrophobic material (for example, as the emulsion in acceptable oil) or ion exchange resin, described compound are configured to sl. sol. The for example sl. sol. salt of derivant.
Additionally, available other pharmaceutical delivery systems.Liposome and emulsion are the transmission that can be used for delivery type i or ii compound Example known to solvent.Although generally with larger toxicity as cost, but still available some organic solvents such as dimethyl sulfoxide. Also can in controlled release system delivery type i compound.In one embodiment, pump (sefton, crc crit.ref can be used Biomed eng., 1987,14,201；Buchwald etc., surgery, 1980,88,507；Saudek etc., n.engl.j med, 1989,321,574).In another embodiment, available macromolecular material is (referring to medical applications of Controlled release, langer and wise (edit), crc pres., boca raton, fla. (1974)； Controlled drug bioavailability, drug product design and performance, smolen and Ball (edits), wiley, new york (1984)；Ranger and peppas, j Macromol.sci.rev.macromol.chem., 1983,23,61；Referring further to levy etc., science1985,228,190； During etc., ann.neurol., 1989,25,351；Howard etc., 1989, j.neurosurg.71,105).Real at another Apply in scheme, controlled release system is placed in the vicinity of the target of the compounds of this invention, such as lung, thus only needs to one of whole-body dose Point (see, e.g., goodson, in medical applications of controlled release, supra, the 2nd Volume, page 115 (1984)).Available other controlled release system (see, e.g., langer, science, 1990,249,1527).
Can be used for providing the applicable excipient (for example, carrier and diluent) of the transmucosal dosage forms being included in the present invention and other Material is known to the technical staff of pharmaceutical field, and depending on the concrete position used by given Pharmaceutical composition or dosage form or side Method.In view of the nontoxic and pharmaceutically acceptable fact, typical excipient includes, but not limited to water, ethanol, ethylene glycol, gathers Ethylene glycol, 1,3 butylene glycol, isopropyl myristate, isopropyl palmitate, mineral oil and its mixture.The reality of this kind of additive Example is known in the art.See, e.g., remington ' s pharmaceutical sciences, the 18th edition, mack Publishing, easton pa (1990).
Also the ph of scalable Pharmaceutical composition or dosage form or described Pharmaceutical composition or dosage form tissue to be applied, to promote The transmission of one or more active component.Similarly, the polarity of scalable solvent carrier, its ionic strength or ionic with promote Enter transmission.Also compound such as stearate can be added in Pharmaceutical composition or dosage form, to beneficially modify one or more The hydrophilic of active component or lipophile carry out faciliated diffusion.Therefore, stearate can be used as the lipid vehicle of described preparation, is used as Emulsifying agent or surfactant, and as transmission accelerator or penetration enhancer.The different salt of described active component, hydration Thing or solvate can be used to adjust the property of generated compositionss further.
5. embodiment
If adopting suitable reagent and substrate, described condition is maintained to vary somewhat, the method that the following example is adopted Can be used for preparing the specifically all compounds in the present invention.To those skilled in the art, do not carry out following providing Many tests, you can be easily achieved this kind of variation.
5.1 embodiments 1:3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic preparation
40g2- chlorotrityl chloride resin (rapp polymer, Germany) is made to be suspended in anhydrous dimethyl formamide (200ml), 10 minutes in, discharge solvent.The 300ml bis- of 3- cyanobenzoic acid (12.71g, 96.4mmol) is added in this resin Methylformamide solution, and it is stirred at room temperature 4 hours.Discharge solvent, with dichloromethane (3 × 200ml × 1 minute), diformazan Base Methanamide (3 × 200ml × 1 minute), methanol (3 × 200ml × 1 minute) and dichloromethane (3 × 200ml × 1 minute) are washed Wash this resin.It is vacuum dried this resin 4 hours.Through cracking a small amount of and triethyl silicane/trifluoroacetic acid/dichloromethane (10/50/ 40) product needed for the resin analysis reacting.Lc/ms (esi) m/z148 [m+h]+With 97% purity.
3- cyanobenzoic acid trityl resin in stirring ethanol (300ml) under room temperature 10 minutes, then remove solvent.To In ethanol (200ml) solution of hydroxylamine hydrochloride (35.81g, 516mmol) add diisopropylethylamine (89.3ml, 516mmol), and at room temperature stir 5 minutes.Add this reactant mixture to this resin, and stir 24 hours at 40 DEG C.Remove Remove solvent, with dichloromethane (3 × 200ml × 10 minute), dimethylformamide (3 × 200ml × 10 minute), methanol (3 × 200ml × 10 minute) and dichloromethane (3 × 200ml × 10 minute) wash this resin.It is vacuum dried this resin 4 hours.Through splitting The product needed for resin analysis that solution was reacted with triethyl silicane/trifluoroacetic acid/dichloromethane (10/50/40) in a small amount.lc/ms (esi) m/z181 [m+h]+With 90% purity.
4- Fluorobenzoyl is added in anhydrous methylene chloride (3ml) suspension of hydoxyamidine resin (500mg, 0.4mmol) Chlorine (95 μ l, 0.8mmol) and diisopropylethylamine (138 μ l, 0.8mmol).Stir this reactant mixture under room temperature all night.Remove Its solvent, with dichloromethane (3 × 10ml × 10 minute), dimethylformamide (3 × 10ml × 10 minute), methanol (3 × 10ml × 10 minutes) and dichloromethane (3 × 10ml × 10 minute) wash this resin.It is vacuum dried this resin 4 hours.Through cracking in a small amount The product needed for resin analysis reacting with triethyl silicane/trifluoroacetic acid/dichloromethane (10/50/40).Lc/ms (esi) m/ z303[m+h]+With 65% purity.
50% 3 in dichloromethane (1.5ml) is added in anhydrous methylene chloride (1.5ml) suspension of acylated resin Fluoroethanoic acid.This reactant mixture is stirred 2 hours under room temperature.Remove this resin, concentrating under reduced pressure filtrate.Residue is made to be dissolved in toluene (4ml), in 10% dimethylformamide in, stir 2 hours then at 130 DEG C.Remove solvent, through described in preparative lc/ms purification Product.Lc/ms (esi) m/z285 [m+h]+With 98% purity.
Prepare following compounds in aforementioned manners.
With electron spray ionisation (esi) through lc/ms analysis of compounds.
5.2 embodiments 2:3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic preparation
K is added in dmf (0.6l) solution of 3- cyanobenzoic acid (44.14g, 300mmol)2co3(62.19g, 450mmol), more at room temperature, stir 30 minutes.Add iodomethane (28ml, 450mmol) with 20 minutes in this suspension, It is stirred for this reactant mixture at room temperature 4 hours.This reactant mixture is poured into 1.2l frozen water, stirs 30 minutes, filter out Its precipitation.Dissolve this white filter cake in methanol (70ml), then reprecipitation in cold water.Obtain the white powder of yield 79% Required product (38g through lc/uv analyze, 99% purity).1h-nmr(cdcl3) δ 8.85 (2h), 8.28 (1h), 8.02 (1h), 4.17(3h).
Under room temperature, in ethanol (500ml) solution of 3- cyano-benzoic acid methyl ester (50g, 310mmol), addition 50% is aqueous Azanol (41ml, 620mmol).Stir this reactant mixture in 100 DEG C 1 hour, removal of solvent under reduced pressure.Make this oiliness residue molten Solution, in 20/80 ethanol/toluene (50ml × 2), then concentrates again.Obtain the white powder of 98% purity (lc/uv) Required ester (61g, quantitative yield).1h-nmr(cdcl3) δ 9.76 (1h), 8.24 (1h), 7.82 (2h), 7.51 (1h), 5.92 (2h), 3.82 (3h).
In 5 DEG C, anhydrous to 3- (n- hydroxyl amidino groups (carbamimidoyl))-essence of Niobe (60g, 310mmol) Add diisopropylethylamine (75ml, 434mmol) in thf (200ml) solution, then add 2- in this mixture with 20 minutes Fluorobenzoyl chloride (48.1ml, 403mmol).This reactant mixture is stirred 1 hour under room temperature.Leach this precipitation, concentrating under reduced pressure This filtrate.Make residue be dissolved in ethyl acetate (400ml), then washed with water (200ml × 2).Removal of solvent under reduced pressure, in hexane In 60% ethyl acetate in crystallize needed for product, generate white solid needed for product (81g, yield 83%).1h-nmr (cdcl3) δ 8.18 (1h), 8.03 (2h), 7.48 (2h), 7.18 (2h), 5.61 (2h), 3.82 (3h).
It is heated at reflux 44g3- (the n-2- Fluorobenzoyl in toluene (500ml) with dean-stark device at 130 DEG C Base amidino groups)-essence of Niobe 4 hours.This reactant mixture is stirred 18 hours at 5 DEG C.Leach white precipitate, concentrate filtrate, then Crystallize in toluene.Obtain the required diazole (38g, yield 92%) of 99% purity (lc/uv) of white solid.
1h-nmr(cdcl3) δ 8.91 (1h), 8.38 (1h), 8.15 (2h), 7.62 (2h), 7.35 (2h), 3.95 (3h).
Thf to 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe (33g, 111mol) (400ml) solution adds the aqueous naoh of 1.5m (100ml, 144mmol).It is heated at reflux this reactant mixture in 100 DEG C 2 hours. Organic solvent is removed under reduced pressure, stirs aqueous solutions 2 hours in 5 DEG C.Filter out white precipitate, concentrate filtrate, precipitate in water. Wash white filter cake with cold water, be then dried with freeze dryer.Obtain the institute of the white powder of 98.6% purity (lc/uv) Need salt (33g, yield 96%).
Thf to 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe (3.3g, 11mmol) (40ml) add the aqueous naoh of 1.5m (10ml, 14mmol) in solution.It is heated at reflux this reactant mixture in 100 DEG C 2 hours.Remove Remove organic solvent, dilute aqueous solution with water (50ml), be then acidified with aqueous hcl.Filter out white precipitate, washed with cold water White filter cake, is then dried with freeze dryer.Obtain 98% purity (lc/uv) white powder required acid (3.0g obtains Rate 96%).242 DEG C of fusing point；
Ir υ 3000 (aromatic c-h), 1710 (c=o)；1h-nmr(d6- dmso) δ 8.31 (1h), 8.18 (2h), 8.08 (1h), 7.88 (2h), 7.51 (2h)；13c-nmr(d6- dmso) δ 172.71,167.38,166.48,161.25,135.80, 132.24,131.79,131.79,131.08,130.91,129.81,127.76,125.48,117.38,111.70；19f-nmr (d6-dmso)δ109.7.
Prepare following compounds in aforementioned manners:
5.3 embodiments 3: promote nonsense suppression and/or the discriminating of compound and the characteristic that adjust translation termination
Test for two kinds of high-throughout screenings described in above 4.2 sections.With based on cell and biochemical test sieve Select compound.Test, resynthesis and re-test compound, with generic chemical structure.Suppressed with external luciferase nonsense again Test determines the property of 3- [2- (4- isopropyl -3- methyl-phenoxv)-acetylamino]-benzoic acid sodium salt.For guaranteeing selectedization The observed nonsense inhibitory activity of compound is not limited to rabbit reticulocyte pilot system, prepares and optimize hela cell extraction Thing (lie＆macdonald, 1999, development126 (22): 4989-4996 and lie＆macdonald, 2000, Biochem.biophys.res.commun.270 (2): 473-481).
5.4 embodiments 4: the characteristic promoting nonsense suppression and producing the compound of functional protein
Aforementioned show, in biochemical test, the compounds of this invention improve nonsense suppression level exceed untreated 3-4 times of extract.For determining whether compound also works in vivo, process protection (harboring) with selected compounds and contain There are the stable cell lines of the luciferase gene of uga nonsense.Make cell growth in being supplemented with 1% Pen .- Strep (p/s) Until -70% converges, process previous natural gift and become (split) 1:1 with the standard medium of 10% fetal bovine serum (fbs).? In the ensuing date, cell is digested by pancreatin, and 40,000 cells are added in each hole of 96- hole tissue culture dishes. Prepare the serial dilutions of each compound, to generate the dose response song crossing 2 logs (30 μm to 0.3 μm) of six points Line.The ultimate density of the dmso solvent in each hole keeps being stable at 1%.It is used as background standard with the cell that 1%dmso was processed, It is used as positive control with the cell that gentamycin was processed.
5.5 embodiments 5:3- [2- (4- isopropyl -3- methyl-phenoxv)-acetyl-amino]-benzoic acid sodium salt changeization Learn the accessibility to the specific nucle in 28s rrna for the dressing agent.
The studies above is it has been shown that other members of gentamycin and the aminoglycoside family reducing translation fidelity link A position to 16s rrna.Through chemical footprinting, uv is crosslinked and nmr is it has been suggested that gentamycin combines in a position of rrna (by nucleoside Sour 1400-1410 and 1490-1500 composition, e.coli numbers) nucleotide 1406,1407,1494 and 1496 on (moazed＆ Noller, 1987, nature327 (6121): 389-394；Woodcock etc., 1991, emboj.10 (10): 3099-3103；With Schroeder etc., 2000, emboj.19:1-9)
The ribosome prepared by hela cell with small molecule (with 100 μm concentration) culture, then uses chemical modifier (sulfur Dimethyl phthalate [dms] and U-2032 [ke]) process.After chemical modification, rrnas extracts through phenol chloroform, ethanol precipitation, uses The oligonucleotide of labelling end hybridizes to the primer extension reaction analysis of the zones of different of three kinds of rrna, and in 6% polypropylene Split on acrylamide gel.For the probe whole 18s of covering (7 oligonucleotide primers) of primer extension, (24 oligomeric for 28s Nucleotide primer) and 5s (primer) rrnas.The tester of these tests includes dmso, and (rrna of dmso induction approaches The comparison sexually revising), paromomycin (18s rrna combine label) and anisomycin (label of 28s rrna combination).
The result of these foot-printing experiments shows, 3- [2- (4- isopropyl -3- methyl-phenoxv)-acetyl-amino]-benzene Formic acid sodium salt changes the accessibility to the specific nucle in 28s rrna for the chemical modifier.More specifically, by 3- [2- (4- isopropyl -3- methyl-phenoxv)-acetyl-amino]-benzoic acid sodium salt protection region include: in (1) peptidyl transferase The conservative region (v domain) of the expression peptide bond formed near the heart, and (2) can with based on vernamycinin b and this Liang Ge area Conservative region in the ii domain that the peptidyl transferase center that domain combines interacts.
5.6 embodiments 6: based on reading over of the Premature stop codon in the disease model of cell
For the effect to the mrnas changing in concrete genetic diseasess for the nonsense inhibiting compound is described, with 3-, [(4- is different for 2- Propyl group -3- methyl-phenoxv)-acetyl-amino] (20 μm) of-benzoic acid sodium salt processes on protected amino acid 1282 (w1282x) The bronchioless epithelial cell line of nonsense codon, the cftr work(of the chloride channel being activated as camp with spq test monitoring Can (yang etc., 1993, hum mol genet.2 (8): 1253-1261 and howard etc., 1996, nat med.2 (4): 467- 469).These tests show, the camp process of these cells leads to the halogenide that spq fluorescence increases and cftr- mediates to flow out Stimulate consistent.When not using compound treated cells or not stimulating described cell with camp, do not observe the increase of fluorescence. These results indicate that when with 3- [2- (4- isopropyl -3- methyl-phenoxv)-acetyl-amino]-sodium benzoate salt treatment, With compound treatment, total length cftr containing the expression of this nonsense allelic also functions to the anion channel stimulating as camp Effect, thus show cystic fibrosis cell lines increase chloride channel activity.
5.7 embodiments 7: with 3- [2- (4- isopropyl -3- methyl-phenoxv)-acetyl-amino]-sodium benzoate salt treatment When the mice of nonsense containing mdx primary cell expression total length dystrophin.
It has been shown that the mutation of mdx mice, the termination in advance of 427kda muscular dystrophy polypeptide, it is 3185 in exon 23 C to t conversion (sicinski etc., 1989, science.244 (4912): 1578-1580) on position.Prepare derivative as before Mus primary skeletal muscle cultures (barton-davis etc., 1999, j clin invest.104 from the mdx mice in 1 day age (4): 375-381).Exist in 3- [2- (4- isopropyl -3- methyl-phenoxv)-acetyl-amino]-benzoic acid sodium salt (20 μm) Under, cultured cells 10 days.Change culture medium within every four days, detect the myotrophy in myoblast culture with aforesaid immunostaining The not presence (barton-davis etc., 1999, j clin invest.104 (4): 375-381) of dystrophin.To muscular dystrophy The c- end of albumen (f19a12) adopts undiluted primary monoclonal antibody, and the rhodamine in conjunction with anti-Mus igg is used as second Antibody.F19a12 antibody can measure the full-length proteins generating through nonsense codon suppression.Leica with the University of Pennsylvania Dmr microscope, digital camera and associated imaging software can observe dyeing.
The reading over of Premature stop codon in 5.8 embodiment 8:mdx mices
As previously mentioned (barton-davis etc., 1999, j clin invest.104 (4): 375-381), numb with implanting Alzet osmotic pumps transmission compound under the skin of liquor-saturated mice.There is provided two dosage 3- [2- (4- isopropyl -3- methyl - Phenoxy group)-acetyl-amino]-benzoic acid sodium salt.Gentamycin is used as positive control, is only used as feminine gender with the pump that solvent is full of Comparison.Pump, equipped with suitable compound, is 10 μm and 20 μm to the calculating dosage being exposed tissue.Calculate and reach tissue exposure Gentamicin concentration is about 200 μm.In testing in the early stage, with, after Patients Under Ketamine Anesthesia mice and blood-letting, processing described animal 14 My god.Then, remove, (ta) muscle before the tibia of refrigeration test animal, for being attached to the dystrophin of stricture of vagina shape muscle Immunofluorescence analysis.Use foregoing immunostaining, measure the presence (barton- of dystrophin in ta flesh Davis etc., 1999, j clin invest.104 (4): 375-381).
5.9 embodiment 9:200mg dose capsule
Table 3 illustrates batch formulation and 200mg single dose unit, i.e. the single formulation preparation of about 40% weight.
Table 3.200mg capsule preparations
Pregelatinized corn starch (spress b-820) and the compounds of this invention component is made to pass through 710 μm and sieve, then with gear Plate insert (baffle insert) loads diffusion mixer, stirs 15 minutes.Make magnesium stearate pass through 210 μm of sieves, add In diffusion mixer.Then with dosator type capsule loader, described mixture is encapsulated in the capsule of #0 specification, every capsule 500mg (in batches for 8400 capsules).
5.10 embodiment 10:100mg peroral dosage forms
Table 4 illustrates a collection of preparation and the single dose unit formulation containing 100mg the compounds of this invention.
Table 4.100mg tablet
Microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the compounds of this invention is made to pass through #30 mesh sieve (about 430 μ-about 655 μ).Make poloxamer(by lenexa, prepared by the jrh biosciences of ks, inc.), surfactant passed through #20 mesh Sieve (about 457 μ-about 1041 μ).Poloxamer is added in 16qt twin shell tumble blenderSurfactant and 0.5kg Cross-linking sodium carboxymethyl cellulose, mix about 5 minutes.Again described mixture is transferred to 3 cubic foot twin shell tumble blenders In, it is added thereto to Microcrystalline Cellulose, mix about 5 minutes.Add compound, remix 25 minutes.This premix is made to pass through It is connected with, in the outlet of roller compactor, the roller compactor that hammer pulverizes device, return again to described rolling blender.By remainder Cross-linking sodium carboxymethyl cellulose and magnesium stearate add described rolling blender in, mix about 3 minutes.Use rotary tablet machine pressure Final mixture processed, every (in batches for 200,000) containing 250mg.
5.11 embodiments 11: aerosol type
Mix the three of the compounds of this invention and 12.6kg deal in the sealing rustless steel container equipped with high-shear mixer Chlorine one fluoromethane, prepares concentrate.Carry out the mixing of about 20 minutes.Again by making described concentrate and products pot (temperature control At 21-27 DEG C, Stress control is in 2.8-4.0bar) in counterweight propellants in described sealing container, preparation Bulk cargo suspension.The 17ml aerosol container being designed with metered amount valve provides the present composition that can suck 100 times.Every container Content is as follows:

Claims (32)

1. a kind of compositionss, it comprises the compound of complete cell and following formula or its pharmaceutically acceptable salt:
Wherein:
Z is the phenyl replacing, and it is replaced selected from following substituent groups by 1-4: halogeno-group, hydroxyl, unsubstituted or by halogen The c replacing1-10Alkoxyl, c1-10Alkylthio group, phenyl, cyano group, azido, amino, by c1-10The single and double substituted amino of alkyl, Nitro and pyrrolidinyl；
c3-7Cycloalkyl；
C that is unsubstituted or being replaced selected from following substituent groups by 1-41-10Alkyl: c1-10Alkoxyl, c1-10Alkylthio group, c3-7 Cycloalkyl, unsubstituted or by halogen or c1-10Phenyl that alkoxyl replaces, the unsubstituted or phenoxy group that is optionally substituted by halogen and Thienyl；
c2-10Alkenyl；
Unsubstituted or by c1-10The piperidyl that alkanoyl replaces；
Unsubstituted or phenyl c by 1-4 halogen substiuted1-10Alkyl；
Benzo [1,3] dioxolyl；
Benzo [1,2,5]Diazole-base；
Pyridine radicals that are unsubstituted or being selected from following substituent groups replacements: halogeno-group, c1-10Alkoxyl, c1-10Alkylthio group, morpholine Base, pyrrolidinyl and piperidyl；
Unsubstituted or by c1-10The furyl that alkyl replaces；
Unsubstituted or by c1-10The thienyl that alkyl replaces；
Benzothienyl；Or
DifferentOxazolyl；
r1It is hydrogen, c1-10Alkyl or-(ch2ch2)nor6；
r2For hydrogen or halogen；
r3For hydrogen；
r4For hydrogen, c1-10Alkoxy or halogen；
r5For hydrogen；
r6For hydrogen or unsubstituted or by c1-10The c that alkoxyl replaces1-10Alkyl, wherein said alkoxyl is originally as unsubstituted Or by c1-10Alkoxyl replaces；
N is the integer of 1-7；
Wherein said complete cell contains the mrna containing Premature stop codon,
Wherein said compositionss are used in vivo improving the work of the albumen coded by the described mrna containing Premature stop codon Property, and described cell is not in human body.
2. the in vivo compositionss of claim 1, wherein said compound has a following formula:
Wherein z is as defined in claim 1；It is hydrogen or halogen with r.
3. the in vivo compositionss of claim 1, wherein said compound is selected from:
3- [5- (4- chloromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- Ethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- tbutyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,6- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,5- pair-trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- dimethoxy-phenylf)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- trifluoromethoxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- pentyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4,5- trimethoxv-henvl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- isobutvl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,3- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro- 5- methylphenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 3- of 4- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 5- of 2- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
5- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base] -2- methoxy-benzoic acid;
3- [5- (2- fluoro- 6- hydroxy-pheny)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- methoxy-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- Mehtoxy-ethoxy)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- { 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyoxyl }-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- 2- [2- (2- Mehtoxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- 2- [2- (2- Hydroxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyl ester;
3- [5- (4- methanesulfonylamino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- azido-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;With
3- [5- (4- benzyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid, and
Its pharmaceutically acceptable salt.
4. the in vivo compositionss of claim 1, wherein said compound be 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole- 3- yl]-benzoic acid, it has a following formula:
.
5. whether a kind of in vivo test compound improves the amount of the albumen coded by the mrna containing Premature stop codon Or the method for functional activity, it includes:
A () uses the following formula: compound of effective dose or the complete cell of its pharmaceutically acceptable salt contact:
Wherein:
Z is the phenyl replacing, and it is replaced selected from following substituent groups by 1-4: halogeno-group, hydroxyl, unsubstituted or by halogen The c replacing1-10Alkoxyl, c1-10Alkylthio group, phenyl, cyano group, azido, amino, by c1-10The single and double substituted amino of alkyl, Nitro and pyrrolidinyl；
c3-7Cycloalkyl；
C that is unsubstituted or being replaced selected from following substituent groups by 1-41-10Alkyl: c1-10Alkoxyl, c1-10Alkylthio group, c3-7 Cycloalkyl, unsubstituted or by halogen or c1-10Phenyl that alkoxyl replaces, the unsubstituted or phenoxy group that is optionally substituted by halogen and Thienyl；
c2-10Alkenyl；
Unsubstituted or by c1-10The piperidyl that alkanoyl replaces；
Unsubstituted or phenyl c by 1-4 halogen substiuted1-10Alkyl；
Benzo [1,3] dioxolyl；
Benzo [1,2,5]Diazole-base；
Pyridine radicals that are unsubstituted or being selected from following substituent groups replacements: halogeno-group, c1-10Alkoxyl, c1-10Alkylthio group, morpholine Base, pyrrolidinyl and piperidyl；
Unsubstituted or by c1-10The furyl that alkyl replaces；
Unsubstituted or by c1-10The thienyl that alkyl replaces；
Benzothienyl；Or
DifferentOxazolyl；
r1It is hydrogen, c1-10Alkyl or-(ch2ch2)nor6；
r2For hydrogen or halogen；
r3For hydrogen；
r4For hydrogen, c1-10Alkoxy or halogen；
r5For hydrogen；
r6For hydrogen or unsubstituted or by c1-10The c that alkoxyl replaces1-10Alkyl, wherein said alkoxyl is originally as unsubstituted Or by c1-10Alkoxyl replaces；
N is the integer of 1-7；With
B () detects amount or the activity of described albumen, if the amount of wherein described albumen or activity phase in the presence of described compound Improve in such a scenario for not depositing, then detect and improve the amount of described albumen or the compound of activity,
Wherein said cell is not in human body.
6. the method for claim 5, wherein said compound has a following formula:
Wherein z is as defined in claim 5；It is hydrogen or halogen with r.
7. the method for claim 5, wherein said compound is selected from:
3- [5- (4- chloromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- Ethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- tbutyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,6- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,5- pair-trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- dimethoxy-phenylf)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- trifluoromethoxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- pentyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4,5- trimethoxv-henvl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- isobutvl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,3- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro- 5- methylphenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 3- of 4- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 5- of 2- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
5- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base] -2- methoxy-benzoic acid;
3- [5- (2- fluoro- 6- hydroxy-pheny)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- methoxy-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- Mehtoxy-ethoxy)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- { 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyoxyl }-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- 2- [2- (2- Mehtoxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- 2- [2- (2- Hydroxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyl ester;
3- [5- (4- methanesulfonylamino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- azido-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;With
3- [5- (4- benzyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid, and
Its pharmaceutically acceptable salt.
8. the method for claim 5, wherein said compound is 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzene Formic acid, it has a following formula:
.
9. a kind of method improving the activity of albumen coded by the mrna containing Premature stop codon, it includes
Cell with the following formula: compound of effective dose or its pharmaceutically acceptable salt contacted in vivo are complete:
Wherein:
Z is the phenyl replacing, and it is replaced selected from following substituent groups by 1-4: halogeno-group, hydroxyl, unsubstituted or by halogen The c replacing1-10Alkoxyl, c1-10Alkylthio group, phenyl, cyano group, azido, amino, by c1-10The single and double substituted amino of alkyl, Nitro and pyrrolidinyl；
c3-7Cycloalkyl；
C that is unsubstituted or being replaced selected from following substituent groups by 1-41-10Alkyl: c1-10Alkoxyl, c1-10Alkylthio group, c3-7 Cycloalkyl, unsubstituted or by halogen or c1-10Phenyl that alkoxyl replaces, the unsubstituted or phenoxy group that is optionally substituted by halogen and Thienyl；
c2-10Alkenyl；
Unsubstituted or by c1-10The piperidyl that alkanoyl replaces；
Unsubstituted or phenyl c by 1-4 halogen substiuted1-10Alkyl；
Benzo [1,3] dioxolyl；
Benzo [1,2,5]Diazole-base；
Pyridine radicals that are unsubstituted or being selected from following substituent groups replacements: halogeno-group, c1-10Alkoxyl, c1-10Alkylthio group, morpholine Base, pyrrolidinyl and piperidyl；
Unsubstituted or by c1-10The furyl that alkyl replaces；
Unsubstituted or by c1-10The thienyl that alkyl replaces；
Benzothienyl；Or
DifferentOxazolyl；
r1It is hydrogen, c1-10Alkyl or-(ch2ch2)nor6；
r2For hydrogen or halogen；
r3For hydrogen；
r4For hydrogen, c1-10Alkoxy or halogen；
r5For hydrogen；
r6For hydrogen or unsubstituted or by c1-10The c that alkoxyl replaces1-10Alkyl, wherein said alkoxyl is originally as unsubstituted Or by c1-10Alkoxyl replaces；
N is the integer of 1-7,
Wherein said cell is not in human body.
10. the method for claim 9, wherein said compound has a following formula:
Wherein z is as defined in claim 9；It is hydrogen or halogen with r.
The method of 11. claim 9, wherein said compound is selected from:
3- [5- (4- chloromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- Ethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- tbutyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,6- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,5- pair-trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- dimethoxy-phenylf)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- trifluoromethoxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- pentyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4,5- trimethoxv-henvl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- isobutvl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,3- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro- 5- methylphenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 3- of 4- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 5- of 2- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
5- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base] -2- methoxy-benzoic acid;
3- [5- (2- fluoro- 6- hydroxy-pheny)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- methoxy-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- Mehtoxy-ethoxy)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- { 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyoxyl }-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- 2- [2- (2- Mehtoxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- 2- [2- (2- Hydroxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyl ester;
3- [5- (4- methanesulfonylamino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- azido-phenyl)-[1,2,4] diazole -3- base]-benzoic acid；With
3- [5- (4- benzyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid, and
Its pharmaceutically acceptable salt.
The method of 12. claim 9, wherein said compound be 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base] - Benzoic acid, it has a following formula:
.
The method that a kind of 13. screenings improve the compound of albumen coded by the mrna containing Premature stop codon, it wraps Include:
A () uses the following formula: compound of effective dose or the complete cell of its pharmaceutically acceptable salt contacted in vivo:
Wherein:
Z is the phenyl replacing, and it is replaced selected from following substituent groups by 1-4: halogeno-group, hydroxyl, unsubstituted or by halogen The c replacing1-10Alkoxyl, c1-10Alkylthio group, phenyl, cyano group, azido, amino, by c1-10The single and double substituted amino of alkyl, Nitro and pyrrolidinyl；
c3-7Cycloalkyl；
C that is unsubstituted or being replaced selected from following substituent groups by 1-41-10Alkyl: c1-10Alkoxyl, c1-10Alkylthio group, c3-7 Cycloalkyl, unsubstituted or by halogen or c1-10Phenyl that alkoxyl replaces, the unsubstituted or phenoxy group that is optionally substituted by halogen and Thienyl；
c2-10Alkenyl；
Unsubstituted or by c1-10The piperidyl that alkanoyl replaces；
Unsubstituted or phenyl c by 1-4 halogen substiuted1-10Alkyl；
Benzo [1,3] dioxolyl；
Benzo [1,2,5]Diazole-base；
Pyridine radicals that are unsubstituted or being selected from following substituent groups replacements: halogeno-group, c1-10Alkoxyl, c1-10Alkylthio group, morpholine Base, pyrrolidinyl and piperidyl；
Unsubstituted or by c1-10The furyl that alkyl replaces；
Unsubstituted or by c1-10The thienyl that alkyl replaces；
Benzothienyl；Or
DifferentOxazolyl；
r1It is hydrogen, c1-10Alkyl or-(ch2ch2)nor6；
r2For hydrogen or halogen；
r3For hydrogen；
r4For hydrogen, c1-10Alkoxy or halogen；
r5For hydrogen；
r6For hydrogen or unsubstituted or by c1-10The c that alkoxyl replaces1-10Alkyl, wherein said alkoxyl is originally as unsubstituted Or by c1-10Alkoxyl replaces；
N is the integer of 1-7；With
B () detects the activity of described albumen, if the activity of wherein described albumen in the presence of described compound with respect to not depositing Improve in such a scenario, then the compound improving described protein active is detected,
Wherein said cell is not in human body.
The method of 14. claim 13, wherein said compound has a following formula:
Wherein z is as defined in claim 13；It is hydrogen or halogen with r.
The method of 15. claim 13, wherein said compound is selected from:
3- [5- (4- chloromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- Ethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- tbutyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,6- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,5- pair-trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- dimethoxy-phenylf)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- trifluoromethoxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- pentyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4,5- trimethoxv-henvl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- isobutvl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,3- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro- 5- methylphenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 3- of 4- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 5- of 2- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
5- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base] -2- methoxy-benzoic acid;
3- [5- (2- fluoro- 6- hydroxy-pheny)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- methoxy-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- Mehtoxy-ethoxy)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- { 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyoxyl }-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- 2- [2- (2- Mehtoxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- 2- [2- (2- Hydroxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyl ester;
3- [5- (4- methanesulfonylamino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- azido-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;With
3- [5- (4- benzyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid, and
Its pharmaceutically acceptable salt.
The method of 16. claim 13, wherein said compound be 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base] - Benzoic acid, it has a following formula:
.
Whether a kind of 17. test compounds improve the side of the activity of albumen coded by the mrna containing Premature stop codon Method, it includes:
A () uses the following formula: compound of effective dose or the complete cell of its pharmaceutically acceptable salt contacted in vivo:
Wherein:
Z is the phenyl replacing, and it is replaced selected from following substituent groups by 1-4: halogeno-group, hydroxyl, unsubstituted or by halogen The c replacing1-10Alkoxyl, c1-10Alkylthio group, phenyl, cyano group, azido, amino, by c1-10The single and double substituted amino of alkyl, Nitro and pyrrolidinyl；
c3-7Cycloalkyl；
C that is unsubstituted or being replaced selected from following substituent groups by 1-41-10Alkyl: c1-10Alkoxyl, c1-10Alkylthio group, c3-7 Cycloalkyl, unsubstituted or by halogen or c1-10Phenyl that alkoxyl replaces, the unsubstituted or phenoxy group that is optionally substituted by halogen and Thienyl；
c2-10Alkenyl；
Unsubstituted or by c1-10The piperidyl that alkanoyl replaces；
Unsubstituted or phenyl c by 1-4 halogen substiuted1-10Alkyl；
Benzo [1,3] dioxolyl；
Benzo [1,2,5]Diazole-base；
Pyridine radicals that are unsubstituted or being selected from following substituent groups replacements: halogeno-group, c1-10Alkoxyl, c1-10Alkylthio group, morpholine Base, pyrrolidinyl and piperidyl；
Unsubstituted or by c1-10The furyl that alkyl replaces；
Unsubstituted or by c1-10The thienyl that alkyl replaces；
Benzothienyl；Or
DifferentOxazolyl；
r1It is hydrogen, c1-10Alkyl or-(ch2ch2)nor6；
r2For hydrogen or halogen；
r3For hydrogen；
r4For hydrogen, c1-10Alkoxy or halogen；
r5For hydrogen；
r6For hydrogen or unsubstituted or by c1-10The c that alkoxyl replaces1-10Alkyl, wherein said alkoxyl is originally as unsubstituted Or by c1-10Alkoxyl replaces；
N is the integer of 1-7；With
B () detects the activity of described albumen, if the activity of wherein described albumen in the presence of described compound with respect to not depositing Improve in such a scenario, then the compound of the activity improving described albumen is detected,
Wherein said cell is not in human body.
The method of 18. claim 17, wherein said compound has a following formula:
Wherein z is as defined in claim 17；It is hydrogen or halogen with r.
The method of 19. claim 17, wherein said compound is selected from:
3- [5- (4- chloromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- Ethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- tbutyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,6- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,5- pair-trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- dimethoxy-phenylf)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- trifluoromethoxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- pentyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4,5- trimethoxv-henvl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- isobutvl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,3- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro- 5- methylphenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 3- of 4- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 5- of 2- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
5- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base] -2- methoxy-benzoic acid;
3- [5- (2- fluoro- 6- hydroxy-pheny)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- methoxy-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- Mehtoxy-ethoxy)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- { 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyoxyl }-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- 2- [2- (2- Mehtoxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- 2- [2- (2- Hydroxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyl ester;
3- [5- (4- methanesulfonylamino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- azido-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;With
3- [5- (4- benzyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid, and
Its pharmaceutically acceptable salt.
The method of 20. claim 17, wherein said compound be 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base] - Benzoic acid, it has a following formula:
.
A kind of 21. methods confirming that compound improves the activity of albumen coded by the mrna containing Premature stop codon, It includes:
A () uses the following formula: compound of effective dose or the complete cell of its pharmaceutically acceptable salt contacted in vivo:
Wherein:
Z is the phenyl replacing, and it is replaced selected from following substituent groups by 1-4: halogeno-group, hydroxyl, unsubstituted or by halogen The c replacing1-10Alkoxyl, c1-10Alkylthio group, phenyl, cyano group, azido, amino, by c1-10The single and double substituted amino of alkyl, Nitro and pyrrolidinyl；
c3-7Cycloalkyl；
C that is unsubstituted or being replaced selected from following substituent groups by 1-41-10Alkyl: c1-10Alkoxyl, c1-10Alkylthio group, c3-7 Cycloalkyl, unsubstituted or by halogen or c1-10Phenyl that alkoxyl replaces, the unsubstituted or phenoxy group that is optionally substituted by halogen and Thienyl；
c2-10Alkenyl；
Unsubstituted or by c1-10The piperidyl that alkanoyl replaces；
Unsubstituted or phenyl c by 1-4 halogen substiuted1-10Alkyl；
Benzo [1,3] dioxolyl；
Benzo [1,2,5]Diazole-base；
Pyridine radicals that are unsubstituted or being selected from following substituent groups replacements: halogeno-group, c1-10Alkoxyl, c1-10Alkylthio group, morpholine Base, pyrrolidinyl and piperidyl；
Unsubstituted or by c1-10The furyl that alkyl replaces；
Unsubstituted or by c1-10The thienyl that alkyl replaces；
Benzothienyl；Or
DifferentOxazolyl；
r1It is hydrogen, c1-10Alkyl or-(ch2ch2)nor6；
r2For hydrogen or halogen；
r3For hydrogen；
r4For hydrogen, c1-10Alkoxy or halogen；
r5For hydrogen；
r6For hydrogen or unsubstituted or by c1-10The c that alkoxyl replaces1-10Alkyl, wherein said alkoxyl is originally as unsubstituted Or by c1-10Alkoxyl replaces；
N is the integer of 1-7；With
B () detects the activity of described albumen, if the activity of wherein described albumen in the presence of described compound with respect to not depositing Improve in such a scenario, then confirm to improve the compound of the activity of described albumen,
Wherein said cell is not in human body.
The method of 22. claim 21, wherein said compound has a following formula:
Wherein z is as defined in claim 21；It is hydrogen or halogen with r.
The method of 23. claim 21, wherein said compound is selected from:
3- [5- (4- chloromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- Ethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- tbutyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- methoxyl group-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,6- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- dimethyl-amino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,5- pair-trifluoromethyl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- dimethoxy-phenylf)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- trifluoromethoxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- pentyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4,5- trimethoxv-henvl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- isobutvl-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,3- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro- 5- methylphenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 3- of 4- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
The fluoro- 5- of 2- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
5- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base] -2- methoxy-benzoic acid;
3- [5- (2- fluoro- 6- hydroxy-pheny)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-essence of Niobe;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- methoxy-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- Mehtoxy-ethoxy)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- { 2- [2- (2- Mehtoxy-ethoxy)-ethoxy Base]-ethyoxyl }-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- (2- 2- [2- (2- Mehtoxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid 2- [2- (2- 2- [2- (2- Hydroxy-ethoxy) - Ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyl ester;
3- [5- (4- methanesulfonylamino-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- azido-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;With
3- [5- (4- benzyloxy-phenyl)-[1,2,4] diazole -3- base]-benzoic acid, and
Its pharmaceutically acceptable salt.
The method of 24. claim 21, wherein said compound be 3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base] - Benzoic acid, it has a following formula:
.
A kind of 25. pharmaceutical compositions for treating the disease related to Premature stop codon or disease, it comprises pharmaceutically Acceptable carrier and the compound of following formula:
Or its pharmaceutically acceptable salt, hydrate, solvate or stereoisomer, wherein:
Z is by the phenyl of one or more halogen substiuted；
r1It is hydrogen；
r2、r3、r4And r5For hydrogen；
The wherein said disease related to Premature stop codon or disease are muscular dystrophy or cystic fibrosises.
The pharmaceutical composition of 26. claim 25, wherein said compound is selected from:
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3,4- difluorophenyl)-[l, 2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 2-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (3- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,5- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,4- difluorophenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (the chloro- phenyl of 3-)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2,6- difluorophenyl)-[l, 2,4] diazole -3- base]-benzoic acid;
3- [5- (4- chloro- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (4- bromo- 2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid;
3- [5- (2- fluoro-phenyl)-[1,2,4] diazole -3- base]-benzoic acid sodium salt；With
Its pharmaceutically acceptable salt, hydrate, solvate or stereoisomer.
The pharmaceutical composition of 27. claim 25, wherein said compound has a following formula:
.
The pharmaceutical composition of any one of 28. claim 25-27, wherein said Premature stop codon is dashed forward by comprising missense The mutation of change, frameshift mutation, insertion mutation, deletion mutation, transition mutations or transversional mutation causes.
The pharmaceutical composition of 29. claim 25, wherein said muscular dystrophy is duchenne muscular dystrophy.
The pharmaceutical composition of 30. claim 25, it is applied to tablets, powder, granule, liquid, suspension, aqueous or capsule Form be orally administered to.
The pharmaceutical composition of 31. claim 25, it contains compound described in 0.1 mg-2000 mg or it is pharmaceutically acceptable Salt, hydrate, solvate or stereoisomer.
The pharmaceutical composition of 32. claim 25, wherein z are (2- fluoro-phenyl);(3,4- difluorophenyl), (the chloro- benzene of 2- Base), (3- fluoro-phenyl), (2,5- difluorophenyl), (2,4- difluorophenyl), (the chloro- phenyl of 3-), (4- fluoro-phenyl), (2,6- Difluorophenyl), (2,3- difluorophenyl), (4- chloro- 2- fluoro-phenyl) or (4- bromo- 2- fluoro-phenyl).
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